chr7-45000368-GC-TT
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_031443.4(CCM2):c.30+5_30+6delinsTT variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 24)
Consequence
CCM2
NM_031443.4 splice_donor_5th_base, intron
NM_031443.4 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.963
Genes affected
CCM2 (HGNC:21708): (CCM2 scaffold protein) This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-45000368-GC-TT is Pathogenic according to our data. Variant chr7-45000368-GC-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCM2 | NM_031443.4 | c.30+5_30+6delinsTT | splice_donor_5th_base_variant, intron_variant | ENST00000258781.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCM2 | ENST00000258781.11 | c.30+5_30+6delinsTT | splice_donor_5th_base_variant, intron_variant | 1 | NM_031443.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 12, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | Observed in individuals with cerebral cavernous malformation (CCM) in published literature and in patients referred for genetic testing at GeneDx (PMID: 21543988); Non-canonical splice site variant demonstrated to result in loss-of-function (PMID: 21543988); This variant is associated with the following publications: (PMID: 23595507, 33729445, 21543988) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 11, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 06, 2023 | 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). - |
Cerebral cavernous malformation 2 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2011 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at