VCV000465574.20 - ClinVar

NM_001164508.2(NEB):c.23967_23970del (p.Pro7990fs)

Germline

Classification

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.

(5)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001164508.2(NEB):c.23967_23970del (p.Pro7990fs)

Variation ID: 465574 Accession: VCV000465574.20

Type and length

Deletion, 4 bp

Location

Cytogenetic: 2q23.3 2: 151501442-151501445 (GRCh38) [ NCBI UCSC ] 2: 152357956-152357959 (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	Dec 26, 2017	Jun 17, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001164508.2:c.23967_23970del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001157980.2:p.Pro7990fs	frameshift
NM_001164507.2:c.23967_23970del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001157979.2:p.Pro7990fs	frameshift
NM_001271208.2:c.24072_24075del	NP_001258137.2:p.Pro8025fs	frameshift
NM_004543.5:c.18825+1348_18825+1351del		intron variant
NC_000002.12:g.151501445_151501448del
NC_000002.11:g.152357959_152357962del
NG_009382.2:g.238043_238046del
LRG_202:g.238043_238046del
LRG_202t1:c.24072_24075del

... more HGVS ... less HGVS

Protein change

P7990fs, P8025fs

Other names

Canonical SPDI

NC_000002.12:151501441:AGGTAGG:AGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA1906174 dbSNP: rs756384471 VarSome

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
Gene	OMIM	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.
Nemaline myopathy 2	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 11, 2024	RCV000549960.11
Arthrogryposis multiplex congenita 6	Likely pathogenic (1)	criteria provided, single submitter	Mar 26, 2024	RCV003476279.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 24, 2023	RCV003488672.2

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.
Uncertain significance (Apr 18, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Nemaline myopathy 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799414.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Likely pathogenic (May 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238307.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Nemaline myopathy 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640731.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 25205138 Comment: This sequence change creates a premature translational stop signal (p.Pro8025Serfs154) in the NEB gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Pro8025Serfs154) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs756384471, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465574). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis multiplex congenita 6 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004200069.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 08, 2022)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	Nemaline myopathy 2 Affected status: yes Allele origin: maternal	Center of Excellence for Medical Genomics, Chulalongkorn University Accession: SCV002546538.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022

Comment:

This sequence change creates a premature translational stop signal (p.Pro8025Serfs*154) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs756384471, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465574). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation update: the spectra of nebulin variants and associated myopathies.	Lehtokari VL	Human mutation	2014	PMID: 25205138

Text-mined citations for rs756384471 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_001164508.2(NEB):c.23967_23970del (p.Pro7990fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs756384471 ...