Variant rs144650652 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031443.4(CCM2):c.*6A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,612,962 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 26 hom. )

Consequence

CCM2
NM_031443.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.17

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=-0.88).

BP6

Variant 7-45076063-A-G is Benign according to our data. Variant chr7-45076063-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 590644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45076063-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00258 (393/152324) while in subpopulation NFE AF= 0.00385 (262/68016). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 393 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCM2	NM_031443.4 linkuse as main transcript	c.*6A>G		3_prime_UTR_variant	10/10	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11 linkuse as main transcript	c.*6A>G		3_prime_UTR_variant	10/10	1	NM_031443.4	ENSP00000258781	P1	Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

394

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00295

AC:

731

AN:

247988

Hom.:

AF XY:

0.00315

AC XY:

425

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.000378

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00341

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00108

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00445

GnomAD4 exome

AF:

0.00353

AC:

5161

AN:

1460638

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

2556

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00338

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.00102

Gnomad4 NFE exome

AF:

0.00405

Gnomad4 OTH exome

AF:

0.00338

GnomAD4 genome

AF:

0.00258

AC:

393

AN:

152324

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

194

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000769

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00385

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00345

Hom.:

Bravo

AF:

0.00283

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	CCM2: BS1, BS2 -

CCM2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.34

DANN

Benign

0.65

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