rs11552377

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V120N) has been classified as Uncertain significance.

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

Publications

41 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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_031443.4

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 VariationId is 261971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 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

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

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

GnomAD2 exomes

AF:

0.147

AC:

36914

AN:

250892

AF XY:

0.152

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 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

African (AFR)

AF:

0.0332

AC:

1112

AN:

33474

American (AMR)

AF:

0.121

AC:

5417

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

5692

AN:

26130

East Asian (EAS)

AF:

0.0777

AC:

3084

AN:

39692

South Asian (SAS)

AF:

0.142

AC:

12214

AN:

86222

European-Finnish (FIN)

AF:

0.127

AC:

6768

AN:

53380

Middle Eastern (MID)

AF:

0.202

AC:

1145

AN:

5662

European-Non Finnish (NFE)

AF:

0.176

AC:

195156

AN:

1111832

Other (OTH)

AF:

0.164

AC:

9917

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

12097

24195

36292

48390

60487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6654

13308

19962

26616

33270

<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:

0.133

AC:

20177

AN:

152202

Hom.:

1653

Cov.:

AF XY:

0.130

AC XY:

9673

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0365

AC:

1517

AN:

41528

American (AMR)

AF:

0.173

AC:

2641

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

778

AN:

3472

East Asian (EAS)

AF:

0.0903

AC:

467

AN:

5172

South Asian (SAS)

AF:

0.142

AC:

685

AN:

4820

European-Finnish (FIN)

AF:

0.121

AC:

1287

AN:

10598

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12277

AN:

67996

Other (OTH)

AF:

0.175

AC:

369

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

872

1744

2616

3488

4360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.166

Hom.:

7105

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

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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) -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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). -

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

(source)

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;.;.;.;.

PhyloP100

1.9

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

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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