This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. This variant also falls at the last nucleotide of exon 175, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202048855, gnomAD 0.006%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 24725366; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.24579G>A. ClinVar contains an entry for this variant (Variation ID: 521691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001164508.2(NEB):c.24579G>A (p.Ser8193=)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001164508.2(NEB):c.24579G>A (p.Ser8193=)
Variation ID: 521691 Accession: VCV000521691.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q23.3 2: 151494161 (GRCh38) [ NCBI UCSC ] 2: 152350675 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 15, 2018 Jul 15, 2024 Mar 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001164508.2:c.24579G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001157980.2:p.Ser8193= synonymous NM_001164507.2:c.24579G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001157979.2:p.Ser8193= synonymous NM_001164508.1:c.24579G>A NM_001271208.2:c.24684G>A NP_001258137.2:p.Ser8228= synonymous NM_004543.5:c.19011G>A NP_004534.3:p.Ser6337= synonymous NC_000002.12:g.151494161C>T NC_000002.11:g.152350675C>T NG_009382.2:g.245327G>A LRG_202:g.245327G>A LRG_202t1:c.24684G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000002.12:151494160:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NEB | - | - |
GRCh38 GRCh37 |
8586 | 11015 | |
| RIF1 | - | - |
GRCh38 GRCh37 |
172 | 2502 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 7, 2017 | RCV000623853.3 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2024 | RCV000820159.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 27, 2021 | RCV002506517.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 22, 2023 | RCV003153763.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2024 | RCV004586841.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 29, 2024 | RCV003465358.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Apr 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742389.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Delayed gross motor development (present) , Generalized hypotonia (present) , Decreased patellar reflex (present) , Muscle weakness (present) , Tongue fasciculations (present) , Feeding difficulties … (more)
Delayed gross motor development (present) , Generalized hypotonia (present) , Decreased patellar reflex (present) , Muscle weakness (present) , Tongue fasciculations (present) , Feeding difficulties (present) , Gastrostomy tube feeding in infancy (present) , Gastroesophageal reflux (present) , Dysphagia (present) , Aspiration (present) , Short lingual frenulum (present) , Failure to thrive (present) , Relative macrocephaly (present) , Prominent forehead (present) , Cleft uvula (present) , High, narrow palate (present) , Wide anterior fontanel (present) , Tented upper lip vermilion (present) , Metatarsus adductus (present) , Microretrognathia (present) (less)
Sex: female
|
|
|
Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Nemaline myopathy 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000960858.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. This variant also falls at the last nucleotide of exon 175, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202048855, gnomAD 0.006%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 24725366; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.24579G>A. ClinVar contains an entry for this variant (Variation ID: 521691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nemaline myopathy 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058735.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521691).It is observed at … (more)
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521691).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Gait disturbance (present) , High, narrow palate (present) , Hypernasal speech (present) , Long ear (present) , Long face (present) , Motor delay (present) , … (more)
Gait disturbance (present) , High, narrow palate (present) , Hypernasal speech (present) , Long ear (present) , Long face (present) , Motor delay (present) , Hypotonia (present) , Muscle weakness (present) , Gowers sign (present) , Myopathy (present) (less)
|
|
|
Likely pathogenic
(Nov 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Nemaline myopathy 2
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060096.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. S8228= has been observed in cases with relevant disease … (more)
NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. S8228= has been observed in cases with relevant disease (PMID: 32222963, 25205138, 23726790, 26562614). Functional assessments of this variant are not available in the literature. S8228= has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Jul 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Nemaline myopathy 2
Arthrogryposis multiplex congenita 6
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811097.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Feb 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003842473.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant located in the final nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both … (more)
Variant located in the final nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138, 32222963, 35081925, 29669168, 24725366) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NEMALINE MYOPATHY 2
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046298.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This synonymous variant affects the last nucleotide of exon 174 of the NEB gene and is predicted to abolish the canonical splice donor site of … (more)
This synonymous variant affects the last nucleotide of exon 174 of the NEB gene and is predicted to abolish the canonical splice donor site of intron 174 by in silico tools (MaxEntScan, GeneSplicer); however, to our knowledge, no RNA-base splicing analysis has been performed to clarify the effect of this alteration on splicing. This variant has been previously reported as a compound heterozygous change or together with another NEB variant, in patients with Nemaline Myopathy (PMID: 24725366, 30467404, 29669168). In one patient, electron microscopy studies showed elongated nemaline bodies in the perinuclear and/or subsarcolemmal areas of muscle fibres (PMID: 24725366). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003428% (8/233398) and thus is presumed to be rare. Based on the available evidence, the c.24579G>A (p.Ser8193=) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: research
|
Nemaline myopathy
Affected status: yes
Allele origin:
maternal
|
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire
Accession: SCV005038590.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
PS3+PM1+PM2+PM3+PP3+PP4+PP5
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis multiplex congenita 6
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004200170.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521691).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. S8228= has been observed in cases with relevant disease (PMID: 32222963, 25205138, 23726790, 26562614). Functional assessments of this variant are not available in the literature. S8228= has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Variant located in the final nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138, 32222963, 35081925, 29669168, 24725366)
Comment:
This synonymous variant affects the last nucleotide of exon 174 of the NEB gene and is predicted to abolish the canonical splice donor site of intron 174 by in silico tools (MaxEntScan, GeneSplicer); however, to our knowledge, no RNA-base splicing analysis has been performed to clarify the effect of this alteration on splicing. This variant has been previously reported as a compound heterozygous change or together with another NEB variant, in patients with Nemaline Myopathy (PMID: 24725366, 30467404, 29669168). In one patient, electron microscopy studies showed elongated nemaline bodies in the perinuclear and/or subsarcolemmal areas of muscle fibres (PMID: 24725366). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003428% (8/233398) and thus is presumed to be rare. Based on the available evidence, the c.24579G>A (p.Ser8193=) variant is classified as Pathogenic.
Comment:
PS3+PM1+PM2+PM3+PP3+PP4+PP5
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. This variant also falls at the last nucleotide of exon 175, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202048855, gnomAD 0.006%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 24725366; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.24579G>A. ClinVar contains an entry for this variant (Variation ID: 521691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521691).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. S8228= has been observed in cases with relevant disease (PMID: 32222963, 25205138, 23726790, 26562614). Functional assessments of this variant are not available in the literature. S8228= has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Variant located in the final nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138, 32222963, 35081925, 29669168, 24725366)
Comment:
This synonymous variant affects the last nucleotide of exon 174 of the NEB gene and is predicted to abolish the canonical splice donor site of intron 174 by in silico tools (MaxEntScan, GeneSplicer); however, to our knowledge, no RNA-base splicing analysis has been performed to clarify the effect of this alteration on splicing. This variant has been previously reported as a compound heterozygous change or together with another NEB variant, in patients with Nemaline Myopathy (PMID: 24725366, 30467404, 29669168). In one patient, electron microscopy studies showed elongated nemaline bodies in the perinuclear and/or subsarcolemmal areas of muscle fibres (PMID: 24725366). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003428% (8/233398) and thus is presumed to be rare. Based on the available evidence, the c.24579G>A (p.Ser8193=) variant is classified as Pathogenic.
Comment:
PS3+PM1+PM2+PM3+PP3+PP4+PP5
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations. | de Feraudy Y | Genome medicine | 2024 | DOI: 10.1186/s13073-024-01353-0 |
| Mutational and clinical spectrum in a cohort of Chinese patients with hereditary nemaline myopathy. | Wang Q | Clinical genetics | 2020 | PMID: 32222963 |
| NEB-related core-rod myopathy with distinct clinical and pathological features. | Park YE | Muscle & nerve | 2016 | PMID: 26562614 |
| Mutation update: the spectra of nebulin variants and associated myopathies. | Lehtokari VL | Human mutation | 2014 | PMID: 25205138 |
| Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype. | Malfatti E | Acta neuropathologica communications | 2014 | PMID: 24725366 |
| Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders. | Chen Z | Neurobiology of aging | 2013 | PMID: 23726790 |
| Human Splicing Finder: an online bioinformatics tool to predict splicing signals. | Desmet FO | Nucleic acids research | 2009 | PMID: 19339519 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs202048855 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.