rs190686229

Variant names:

Variant summary

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

The NM_031443.4(CCM2):c.1054+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,610,342 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 18 hom. )

Consequence

CCM2
NM_031443.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.296

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-45074420-C-T is Benign according to our data. Variant chr7-45074420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45074420-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (366/152318) while in subpopulation NFE AF= 0.00429 (292/68016). AF 95% confidence interval is 0.00389. There are 0 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4 link	c.1054+12C>T		intron_variant	Intron 9 of 9	ENST00000258781.11	NP_113631.1	Q9BSQ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11 link	c.1054+12C>T		intron_variant	Intron 9 of 9	1	NM_031443.4	ENSP00000258781.7		Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

366

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00256

AC:

628

AN:

245106

Hom.:

AF XY:

0.00279

AC XY:

371

AN XY:

132912

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00141

Gnomad ASJ exome

AF:

0.00464

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.00420

Gnomad OTH exome

AF:

0.00217

GnomAD4 exome

AF:

0.00440

AC:

6412

AN:

1458024

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

3140

AN XY:

725196

show subpopulations

Gnomad4 AFR exome

AF:

0.000898

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.00545

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.000360

Gnomad4 NFE exome

AF:

0.00522

Gnomad4 OTH exome

AF:

0.00418

GnomAD4 genome

AF:

0.00240

AC:

366

AN:

152318

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

156

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00337

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebral cavernous malformation 2

Benign:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.77

DANN

Benign

0.41

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