7-45000336-G-A

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

Scores

4
4
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCM2NM_031443.4 linkc.3G>A p.Met1? start_lost Exon 1 of 10 ENST00000258781.11 NP_113631.1 Q9BSQ5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCM2ENST00000258781.11 linkc.3G>A p.Met1? start_lost Exon 1 of 10 1 NM_031443.4 ENSP00000258781.7 Q9BSQ5-1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1145190
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
552686
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.25
T;.;.
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.0035
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Uncertain
0.52
D;D;D
MetaSVM
Benign
-0.93
T
PROVEAN
Uncertain
-2.5
D;N;N
REVEL
Benign
0.23
Sift
Pathogenic
0.0
D;D;T
Sift4G
Pathogenic
0.0
D;D;T
Polyphen
0.0050
B;.;.
Vest4
0.66
MutPred
0.55
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
0.49
ClinPred
0.82
D
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-45039935; API