rs137852843

chr7-45068563-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_031443.4(CCM2):c.593T>G(p.Leu198Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.45

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 7-45068563-T-G is Pathogenic according to our data. Variant chr7-45068563-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2686.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.593T>G	p.Leu198Arg	missense_variant	5/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.593T>G	p.Leu198Arg	missense_variant	5/10	1	NM_031443.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebral cavernous malformation 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.85	P;.;.;.
Vest4		0.98
MutPred		0.53		Loss of stability (P = 0.0569);.;.;.;
MVP		0.73
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852843; hg19: chr7-45108162;