rs148244188
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_031443.4(CCM2):c.246C>T(p.Pro82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,334 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 14 hom. )
Consequence
CCM2
NM_031443.4 synonymous
NM_031443.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0720
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 Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
?
Variant 7-45063959-C-T is Benign according to our data. Variant chr7-45063959-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45063959-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.072 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (267/152202) while in subpopulation NFE AF= 0.00298 (203/68008). AF 95% confidence interval is 0.00265. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 267 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCM2 | NM_031443.4 | c.246C>T | p.Pro82= | synonymous_variant | 3/10 | ENST00000258781.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCM2 | ENST00000258781.11 | c.246C>T | p.Pro82= | synonymous_variant | 3/10 | 1 | NM_031443.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00176 AC: 267AN: 152084Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00186 AC: 468AN: 251466Hom.: 1 AF XY: 0.00188 AC XY: 256AN XY: 135910
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GnomAD4 exome AF: 0.00268 AC: 3917AN: 1461132Hom.: 14 Cov.: 30 AF XY: 0.00265 AC XY: 1929AN XY: 726916
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GnomAD4 genome ? AF: 0.00175 AC: 267AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122AN XY: 74414
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | CCM2: BP4, BP7, BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 05, 2017 | Although the c.246C>T variant (rs148244188) has not been reported in the medical literature, it is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.3% in the non-Finnish European population (identified in 389 out of 126,714 chromosomes; 1 homozygote) and is classified as likely benign in ClinVar (Variant ID: 261968). The cytosine at nucleotide 246 is not conserved, and computational analyses predict that this variant does not affect splicing of the CCM2 mRNA (Alamut software v2.10.0). Therefore, based on the available information, the c.246C>T variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Cerebral cavernous malformation 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at