rs2289366

Positions:

chr7-45073522-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.866G>A(p.Ser289Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,166 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 382 hom. )

Consequence

CCM2
NM_031443.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.69

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=0.0018657148).

BP6

Variant 7-45073522-G-A is Benign according to our data. Variant chr7-45073522-G-A is described in ClinVar as [Benign]. Clinvar id is 261974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45073522-G-A is described in Lovd as [Likely_benign]. Variant chr7-45073522-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 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.866G>A	p.Ser289Asn	missense_variant	8/10	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.866G>A	p.Ser289Asn	missense_variant	8/10	1	NM_031443.4	ENSP00000258781.7		Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00738

AC:

1123

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0615

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00712

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.0173

AC:

4320

AN:

250050

Hom.:

302

AF XY:

0.0135

AC XY:

1832

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00680

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.000562

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00951

GnomAD4 exome

AF:

0.00405

AC:

5922

AN:

1460828

Hom.:

382

Cov.:

AF XY:

0.00359

AC XY:

2607

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00829

Gnomad4 SAS exome

AF:

0.00228

Gnomad4 FIN exome

AF:

0.000400

Gnomad4 NFE exome

AF:

0.000141

Gnomad4 OTH exome

AF:

0.00374

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152338

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

596

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.0623

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00714

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00494

Hom.:

Bravo

AF:

0.0130

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0130

AC:

1574

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2024	- -

Cerebral cavernous malformation 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28655553) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.074

T;T;T;T;D;T

Sift4G

Uncertain

0.051

T;D;D;D;D;D

Polyphen

0.87

P;.;.;.;.;.

Vest4

0.20

MPC

0.68

ClinPred

0.026

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.47

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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