7-45000368-GC-TT

Position:

• chr7-45000368-GC-TT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• 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]

ACMG classification

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	Protein	UniProt
CCM2	NM_031443.4	c.30+5_30+6delinsTT		splice_donor_5th_base_variant, intron_variant		ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.30+5_30+6delinsTT		splice_donor_5th_base_variant, intron_variant		1	NM_031443.4	ENSP00000258781	P1

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2024	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) -
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:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

CCM2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044623; hg19: chr7-45039967;