rs2289367

chr7-45073571-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_031443.4(CCM2):c.915G>A(p.Thr305=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,602,280 control chromosomes in the GnomAD database, including 39,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3852 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35310 hom.)
• Consequence: CCM2 NM_031443.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.17

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 -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 7-45073571-G-A is Benign according to our data. Variant chr7-45073571-G-A is described in ClinVar as [Benign]. Clinvar id is 261975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45073571-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.915G>A	p.Thr305=	splice_region_variant, synonymous_variant	8/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.915G>A	p.Thr305=	splice_region_variant, synonymous_variant	8/10	1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34144 AN: 152004 Hom.: 3847 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.231 AC: 56546 AN: 245312 Hom.: 6916 AF XY: 0.223 AC XY: 29710 AN XY: 133244

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.217 AC: 315144 AN: 1450158 Hom.: 35310 Cov.: 30 AF XY: 0.216 AC XY: 155638 AN XY: 721236

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.225 AC: 34179 AN: 152122 Hom.: 3852 Cov.: 32 AF XY: 0.224 AC XY: 16675 AN XY: 74382

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.189

Alfa AF: 0.210 Hom.: 5675

Bravo AF: 0.233

Asia WGS AF: 0.197 AC: 688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27708576) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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: rs2289367; hg19: chr7-45113170; COSMIC: COSV51849946; COSMIC: COSV51849946;