rs2107732

chr7-45038379-G-Achr7-45038379-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031443.4(CCM2):c.157G>A(p.Val53Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0791 in 1,614,010 control chromosomes in the GnomAD database, including 5,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V53V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.060 (386 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5378 hom.)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.09

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013820231).
• BP6: Variant 7-45038379-G-A is Benign according to our data. Variant chr7-45038379-G-A is described in ClinVar as [Benign]. Clinvar id is 261965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45038379-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.157G>A	p.Val53Ile	missense_variant	2/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.157G>A	p.Val53Ile	missense_variant	2/10	1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.0604 AC: 9192 AN: 152116 Hom.: 386 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.0712

GnomAD3 exomes AF: 0.0631 AC: 15863 AN: 251384 Hom.: 661 AF XY: 0.0635 AC XY: 8628 AN XY: 135870

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0344

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0811 AC: 118554 AN: 1461776 Hom.: 5378 Cov.: 33 AF XY: 0.0804 AC XY: 58488 AN XY: 727192

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0717

Gnomad4 NFE exome AF: 0.0915

Gnomad4 OTH exome AF: 0.0799

GnomAD4 genome AF: 0.0604 AC: 9189 AN: 152234 Hom.: 386 Cov.: 32 AF XY: 0.0569 AC XY: 4236 AN XY: 74440

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.0544

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.0598

Gnomad4 NFE AF: 0.0938

Gnomad4 OTH AF: 0.0700

Alfa AF: 0.0829 Hom.: 969

Bravo AF: 0.0589

TwinsUK AF: 0.0936 AC: 347

ALSPAC AF: 0.0944 AC: 364

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0897 AC: 771

ExAC AF: 0.0628 AC: 7628

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0829

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 12, 2016	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 09, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	19
Dann	Benign	0.84
DEOGEN2	Benign	0.041	T;.;T;.;T
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.23	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.87	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.18	B;.;.;.;.
Vest4		0.054
MPC		0.29
ClinPred		0.047	T
GERP RS		5.4
Varity_R		0.053
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs2107732; hg19: chr7-45077978; COSMIC: COSV104578961;