rs200358025
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2
The NM_031443.4(CCM2):c.568G>A(p.Val190Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
CCM2
NM_031443.4 missense
NM_031443.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 4.80
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 -10 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_031443.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.014697552).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152306) while in subpopulation EAS AF= 0.00232 (12/5180). AF 95% confidence interval is 0.00134. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCM2 | NM_031443.4 | c.568G>A | p.Val190Met | missense_variant | 5/10 | ENST00000258781.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCM2 | ENST00000258781.11 | c.568G>A | p.Val190Met | missense_variant | 5/10 | 1 | NM_031443.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152188Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000227 AC: 57AN: 251396Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135886
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727224
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 14, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | CCM2: BS1, BS2 - |
Cerebral cavernous malformation 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;.;.;.
Vest4
MVP
MPC
0.93
ClinPred
T
GERP RS
Varity_R
gMVP
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