rs148244188

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_031443.4(CCM2):c.246C>T(p.Pro82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,334 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 14 hom. )

Consequence

CCM2
NM_031443.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0720

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 7-45063959-C-T is Benign according to our data. Variant chr7-45063959-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45063959-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.072 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (267/152202) while in subpopulation NFE AF= 0.00298 (203/68008). AF 95% confidence interval is 0.00265. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4 linkuse as main transcript	c.246C>T	p.Pro82=	synonymous_variant	3/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11 linkuse as main transcript	c.246C>T	p.Pro82=	synonymous_variant	3/10	1	NM_031443.4	P1	Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00186

AC:

468

AN:

251466

Hom.:

AF XY:

0.00188

AC XY:

256

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.00299

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00268

AC:

3917

AN:

1461132

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1929

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.00317

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152202

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00172

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2017	Although the c.246C>T variant (rs148244188) has not been reported in the medical literature, it is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.3% in the non-Finnish European population (identified in 389 out of 126,714 chromosomes; 1 homozygote) and is classified as likely benign in ClinVar (Variant ID: 261968). The cytosine at nucleotide 246 is not conserved, and computational analyses predict that this variant does not affect splicing of the CCM2 mRNA (Alamut software v2.10.0). Therefore, based on the available information, the c.246C>T variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CCM2: BP4, BP7 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cerebral cavernous malformation 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

Cadd

Benign

7.1

Dann

Benign

0.56

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