7-45038379-G-A

Position:

chr7-45038379-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.060 ( 386 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5378 hom. )

Consequence

CCM2
NM_031443.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.09

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]

CCM2 links:

CCM2 (HGNC:):

CCM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CCM2	NM_031443.4 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	2/10	ENST00000258781.11	NP_113631.1	Q9BSQ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	2/10	1	NM_031443.4	ENSP00000258781.7		Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.0604

AC:

9192

AN:

152116

Hom.:

386

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0804

AC XY:

58488

AN XY:

727192

show subpopulations

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.:

AF XY:

0.0569

AC XY:

4236

AN XY:

74440

show subpopulations

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:

ESP6500EA

AF:

0.0897

AC:

771

ExAC

AF:

0.0628

AC:

7628

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0887

EpiControl

AF:

0.0829

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation 2

Benign:4

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 12, 2016	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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

BayesDel_noAF

Benign

-0.57

CADD

Benign

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

LIST_S2

Benign

0.81

T;T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;N;.;.;.

PrimateAI

Uncertain

0.48

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over