7-45000336-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_031443.4(CCM2):c.3G>A(p.Met1?) variant causes a start lost 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 25)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CCM2
NM_031443.4 start_lost
NM_031443.4 start_lost
Scores
4
4
8
Clinical Significance
Conservation
PhyloP100: 2.37
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.
PVS1
Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 906 CDS bases. Genomic position: 45073562. Lost 0.679 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 25
GnomAD3 genomes
Cov.:
25
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1145190Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 552686
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1145190
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
552686
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 25
GnomAD4 genome
Cov.:
25
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Jun 30, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
PROVEAN
Uncertain
D;N;N
REVEL
Benign
Sift
Pathogenic
D;D;T
Sift4G
Pathogenic
D;D;T
Polyphen
B;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.1331);Gain of catalytic residue at M1 (P = 0.1331);Gain of catalytic residue at M1 (P = 0.1331);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.