NM_031443.4:c.804-5C>T

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.804-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,610,566 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 12 hom. )

Consequence

CCM2
NM_031443.4 splice_region, intron

Scores

Splicing: ADA: 0.00001679

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.225

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=-0.83).

BP6

Variant 7-45073455-C-T is Benign according to our data. Variant chr7-45073455-C-T is described in ClinVar as [Benign]. Clinvar id is 585628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45073455-C-T is described in Lovd as [Benign]. Variant chr7-45073455-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (284/152372) while in subpopulation NFE AF= 0.00338 (230/68042). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 284 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4 link	c.804-5C>T		splice_region_variant, intron_variant	Intron 7 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.804-5C>T		splice_region_variant, intron_variant	Intron 7 of 9	1	NM_031443.4	ENSP00000258781.7		Q9BSQ5-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00232

AC:

581

AN:

250110

Hom.:

AF XY:

0.00246

AC XY:

334

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.000651

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00293

AC:

4269

AN:

1458194

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

2154

AN XY:

725658

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.000832

Gnomad4 NFE exome

AF:

0.00356

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00186

AC:

284

AN:

152372

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00175

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 29, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCM2: BS1, BS2 -

Cerebral cavernous malformation 2

Benign:2

Jun 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CCM2-related disorder

Benign:1

Apr 28, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-0.83

CADD

Benign

0.41

DANN

Benign

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0020

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