Variant rs2304691 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031443.4(CCM2):c.1260G>A(p.Glu420=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,174 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 17 hom. )

Consequence

CCM2
NM_031443.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.63

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 7-45075982-G-A is Benign according to our data. Variant chr7-45075982-G-A is described in ClinVar as [Benign]. Clinvar id is 590646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00179 (272/152340) while in subpopulation EAS AF= 0.0257 (133/5178). AF 95% confidence interval is 0.0221. There are 0 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4 linkuse as main transcript	c.1260G>A	p.Glu420=	synonymous_variant	10/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11 linkuse as main transcript	c.1260G>A	p.Glu420=	synonymous_variant	10/10	1	NM_031443.4	P1	Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0258

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00338

AC:

845

AN:

249662

Hom.:

AF XY:

0.00288

AC XY:

390

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00819

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0295

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00111

AC:

1623

AN:

1460834

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

766

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00821

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0290

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00179

AC:

272

AN:

152340

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0257

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.00199

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebral cavernous malformation 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.2

DANN

Benign

0.85

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