rs2107732

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.09

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

cerebral cavernous malformation 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
famililal cerebral cavernous malformations
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CCM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 261965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CCM2	NM_031443.4 link	c.157G>A	p.Val53Ile	missense_variant	Exon 2 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.157G>A	p.Val53Ile	missense_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.0631

AC:

15863

AN:

251384

AF XY:

0.0635

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 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

African (AFR)

AF:

0.0119

AC:

398

AN:

33480

American (AMR)

AF:

0.0393

AC:

1756

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2713

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0344

AC:

2970

AN:

86258

European-Finnish (FIN)

AF:

0.0717

AC:

3830

AN:

53380

Middle Eastern (MID)

AF:

0.0563

AC:

325

AN:

5768

European-Non Finnish (NFE)

AF:

0.0915

AC:

101734

AN:

1111940

Other (OTH)

AF:

0.0799

AC:

4823

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6020

12040

18061

24081

30101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3612

7224

10836

14448

18060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0604

AC:

9189

AN:

152234

Hom.:

386

Cov.:

AF XY:

0.0569

AC XY:

4236

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0157

AC:

654

AN:

41546

American (AMR)

AF:

0.0544

AC:

831

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0988

AC:

343

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0303

AC:

146

AN:

4822

European-Finnish (FIN)

AF:

0.0598

AC:

634

AN:

10600

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0938

AC:

6377

AN:

68004

Other (OTH)

AF:

0.0700

AC:

148

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

428

857

1285

1714

2142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0802

Hom.:

1480

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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Jul 12, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 09, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

7.1

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

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over