rs11552377

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_031443.4(CCM2):c.358G>A(p.Val120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,656 control chromosomes in the GnomAD database, including 22,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1653 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20872 hom. )

Consequence

CCM2
NM_031443.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.90

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:

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=0.0017606616).

BP6

Variant 7-45064532-G-A is Benign according to our data. Variant chr7-45064532-G-A is described in ClinVar as [Benign]. Clinvar id is 261971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45064532-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4 link	c.358G>A	p.Val120Ile	missense_variant	Exon 4 of 10	ENST00000258781.11	NP_113631.1	Q9BSQ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11 link	c.358G>A	p.Val120Ile	missense_variant	Exon 4 of 10	1	NM_031443.4	ENSP00000258781.7		Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20177

AN:

152084

Hom.:

1655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0366

Gnomad AMI

AF:

0.100

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.0905

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.174

GnomAD3 exomes

AF:

0.147

AC:

36914

AN:

250892

Hom.:

3077

AF XY:

0.152

AC XY:

20652

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.0343

Gnomad AMR exome

AF:

0.117

Gnomad ASJ exome

AF:

0.216

Gnomad EAS exome

AF:

0.0923

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.165

AC:

240505

AN:

1461454

Hom.:

20872

Cov.:

AF XY:

0.165

AC XY:

120294

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0332

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.0777

Gnomad4 SAS exome

AF:

0.142

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.176

Gnomad4 OTH exome

AF:

0.164

GnomAD4 genome

AF:

0.133

AC:

20177

AN:

152202

Hom.:

1653

Cov.:

AF XY:

0.130

AC XY:

9673

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0365

Gnomad4 AMR

AF:

0.173

Gnomad4 ASJ

AF:

0.224

Gnomad4 EAS

AF:

0.0903

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.174

Hom.:

5324

Bravo

AF:

0.128

TwinsUK

AF:

0.179

AC:

664

ALSPAC

AF:

0.176

AC:

678

ESP6500AA

AF:

0.0399

AC:

176

ESP6500EA

AF:

0.184

AC:

1582

ExAC

AF:

0.145

AC:

17648

Asia WGS

AF:

0.137

AC:

476

AN:

3478

EpiCase

AF:

0.193

EpiControl

AF:

0.192

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation 2

Benign:4

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28000143, 20419355, 23485406) -

Sep 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CCM2-related disorder

Benign:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.035

T;.;.;T;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

T;T;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;.;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

0.26

N;N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.86

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.015

B;.;.;.;.;.

Vest4

0.044

MPC

0.25

ClinPred

0.011

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

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