Variant chr7-45027668-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_031443.4(CCM2):c.31-10585G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,234 control chromosomes in the GnomAD database, including 40,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4035 hom., cov: 32)

Exomes 𝑓: 0.22 ( 36128 hom. )

Consequence

CCM2
NM_031443.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.819

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 7-45027668-G-C is Benign according to our data. Variant chr7-45027668-G-C is described in ClinVar as [Benign]. Clinvar id is 522245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45027668-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4 linkuse as main transcript	c.31-10585G>C		intron_variant		ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11 linkuse as main transcript	c.31-10585G>C		intron_variant		1	NM_031443.4	P1	Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34856

AN:

151862

Hom.:

4032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.193

GnomAD3 exomes

AF:

0.232

AC:

58268

AN:

251014

Hom.:

7269

AF XY:

0.224

AC XY:

30432

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.267

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.199

Gnomad SAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.207

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.219

AC:

319760

AN:

1461252

Hom.:

36128

Cov.:

AF XY:

0.217

AC XY:

157861

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.274

Gnomad4 AMR exome

AF:

0.347

Gnomad4 ASJ exome

AF:

0.181

Gnomad4 EAS exome

AF:

0.181

Gnomad4 SAS exome

AF:

0.216

Gnomad4 FIN exome

AF:

0.206

Gnomad4 NFE exome

AF:

0.216

Gnomad4 OTH exome

AF:

0.209

GnomAD4 genome

AF:

0.230

AC:

34887

AN:

151982

Hom.:

4035

Cov.:

AF XY:

0.229

AC XY:

16988

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.271

Gnomad4 AMR

AF:

0.255

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.194

Gnomad4 SAS

AF:

0.212

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.211

Gnomad4 OTH

AF:

0.191

Alfa

AF:

0.146

Hom.:

354

Bravo

AF:

0.239

Asia WGS

AF:

0.198

AC:

692

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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