rs190686229

Positions:

• chr7-45074420-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000258781.11(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 ENST00000258781.11 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.296

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CCM2	NM_031443.4	c.1054+12C>T		intron_variant		ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.1054+12C>T		intron_variant		1	NM_031443.4	ENSP00000258781	P1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152200 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.00279 AC XY: 371 AN XY: 132912

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.: 18 Cov.: 30 AF XY: 0.00433 AC XY: 3140 AN XY: 725196

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.: 0 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74488

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.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2017	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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -

Cerebral cavernous malformation 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

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

Other links and lift over

dbSNP: rs190686229; hg19: chr7-45114019;