The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 21543988, 23595507).
ClinVar Genomic variation as it relates to human health
NM_031443.4(CCM2):c.30+5_30+6delinsTT
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_031443.4(CCM2):c.30+5_30+6delinsTT
Variation ID: 193463 Accession: VCV000193463.23
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 7p13 7: 45000368-45000369 (GRCh38) [ NCBI UCSC ] 7: 45039967-45039968 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 28, 2015 Oct 8, 2024 Aug 2, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_031443.4:c.30+5_30+6delinsTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001167934.2:c.30+5_30+6delinsTT intron variant NM_001167935.2:c.30+5_30+6delinsTT intron variant NM_001363458.2:c.30+5_30+6delinsTT intron variant NM_001363459.2:c.30+5_30+6delinsTT intron variant NM_031443.3:c.30+5_30+6delGCinsTT NC_000007.14:g.45000368_45000369delinsTT NC_000007.13:g.45039967_45039968delinsTT NG_016295.1:g.5181_5182delinsTT LRG_664:g.5181_5182delinsTT LRG_664t2:c.30+5_30+6delinsTT - Protein change
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- Other names
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- Canonical SPDI
- NC_000007.14:45000367:GC:TT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| CCM2 | - | - |
GRCh38 GRCh37 |
316 | 369 | |
| LOC129998395 | - | - | - | GRCh38 | - | 28 |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Jan 19, 2024 | RCV000173535.15 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2024 | RCV000339043.19 | |
|
CCM2-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jul 5, 2024 | RCV004751328.1 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jun 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000612714.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 21543988, 23595507). (less)
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Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cerebral cavernous malformation 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000644923.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 1 of the CCM2 gene. It does not directly change the encoded amino acid sequence of the CCM2 protein. … (more)
This sequence change falls in intron 1 of the CCM2 gene. It does not directly change the encoded amino acid sequence of the CCM2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of cerebral cavernous malformations (PMID: 21543988, 23595507; Invitae). ClinVar contains an entry for this variant (Variation ID: 193463). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21543988). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224657.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329216.12
First in ClinVar: Dec 06, 2016 Last updated: Oct 08, 2024 |
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 21543988, 23595507); This variant is associated with the following publications: (PMID: 23595507, 33729445, 21543988)
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Pathogenic
(Jul 01, 2011)
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no assertion criteria provided
Method: literature only
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CEREBRAL CAVERNOUS MALFORMATIONS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044957.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023 |
Comment on evidence:
In 7 apparently unrelated probands from 10 different kindreds of Ashkenazi Jewish descent segregating CCM2 (CCM2; 603284), Gallione et al. (2011) identified a heterozygous 2-bp … (more)
In 7 apparently unrelated probands from 10 different kindreds of Ashkenazi Jewish descent segregating CCM2 (CCM2; 603284), Gallione et al. (2011) identified a heterozygous 2-bp change in the CCM2 gene caused by deletion of a GC pair and insertion of a TT pair near the splice donor site of exon 1 (30+5_6delinsTT). The 2-bp change segregated with affected status in the study families. Transcripts arising from the normal and mutant alleles were examined by RT-PCR from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. The 2-bp change, when tested in this in vitro synthetic splicing system, altered splice donor site utilization. RT-PCR revealed loss of the transcript allele that was in phase with the mutation. Gallione et al. (2011) concluded that this 2-bp change in CCM2 disrupted proper splice donor utilization leading to a degraded transcript. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common SNP haplotype in affected individuals that demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. (less)
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Pathogenic
(Jul 05, 2024)
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no assertion criteria provided
Method: clinical testing
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CCM2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000852918.2
First in ClinVar: Dec 19, 2017 Last updated: Oct 08, 2024 |
Comment:
The CCM2 c.30+5_30+6delinsTT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported as a founder variant in individuals … (more)
The CCM2 c.30+5_30+6delinsTT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported as a founder variant in individuals of Ashkenazi Jewish ancestry and functional studies have shown that it affects splicing (Gallione et al. 2011. PubMed ID: 21543988). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/193463). Based on this evidence, we interpret this variant as pathogenic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Cerebral cavernous malformation 2
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000297820.2
First in ClinVar: Jun 28, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This sequence change falls in intron 1 of the CCM2 gene. It does not directly change the encoded amino acid sequence of the CCM2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of cerebral cavernous malformations (PMID: 21543988, 23595507; Invitae). ClinVar contains an entry for this variant (Variation ID: 193463). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21543988). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 21543988, 23595507); This variant is associated with the following publications: (PMID: 23595507, 33729445, 21543988)
Comment:
The CCM2 c.30+5_30+6delinsTT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported as a founder variant in individuals of Ashkenazi Jewish ancestry and functional studies have shown that it affects splicing (Gallione et al. 2011. PubMed ID: 21543988). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/193463). Based on this evidence, we interpret this variant 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:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 21543988, 23595507).
Comment:
This sequence change falls in intron 1 of the CCM2 gene. It does not directly change the encoded amino acid sequence of the CCM2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of cerebral cavernous malformations (PMID: 21543988, 23595507; Invitae). ClinVar contains an entry for this variant (Variation ID: 193463). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21543988). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 21543988, 23595507); This variant is associated with the following publications: (PMID: 23595507, 33729445, 21543988)
Comment:
The CCM2 c.30+5_30+6delinsTT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported as a founder variant in individuals of Ashkenazi Jewish ancestry and functional studies have shown that it affects splicing (Gallione et al. 2011. PubMed ID: 21543988). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/193463). Based on this evidence, we interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Familial Cerebral Cavernous Malformations. | Adam MP | - | 2023 | PMID: 20301470 |
| Cerebral Cavernous Malformation 2 Syndrome Presenting With Retinal Cavernous Hemangioma and Sixth Cranial Nerve Palsy. | Khan MJ | JAMA ophthalmology | 2021 | PMID: 33729445 |
| CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions. | Riant F | Neurogenetics | 2013 | PMID: 23595507 |
| A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. | Gallione CJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21543988 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CCM2 | - | - | - | - |
Text-mined citations for rs797044623 ...
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 Oct 13, 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.