rs2304689

Variant names:

• chr7-45063882-A-G
• rs2304689
• NM_031443.4:c.205-36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031443.4(CCM2):​c.205-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,443,514 control chromosomes in the GnomAD database, including 35,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3818 hom., cov: 31)
  • Exomes 𝑓: 0.22 (31669 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.908
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-45063882-A-G is Benign according to our data. Variant chr7-45063882-A-G is described in ClinVar as Benign. ClinVar VariationId is 261967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.205-36A>G		intron_variant	Intron 2 of 9	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.205-36A>G		intron_variant	Intron 2 of 9	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes AF: 0.225 AC: 33992 AN: 151360 Hom.: 3813 Cov.: 31

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.230 AC: 57695 AN: 250714 AF XY: 0.223

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.218 AC: 281121 AN: 1292036 Hom.: 31669 Cov.: 18 AF XY: 0.216 AC XY: 140664 AN XY: 652286

African (AFR) AF: 0.255 AC: 7669 AN: 30090

American (AMR) AF: 0.345 AC: 15353 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4508 AN: 25074

East Asian (EAS) AF: 0.177 AC: 6894 AN: 38848

South Asian (SAS) AF: 0.217 AC: 17978 AN: 82926

European-Finnish (FIN) AF: 0.206 AC: 10921 AN: 53052

Middle Eastern (MID) AF: 0.183 AC: 998 AN: 5464

European-Non Finnish (NFE) AF: 0.215 AC: 205479 AN: 957422

Other (OTH) AF: 0.207 AC: 11321 AN: 54676

GnomAD4 genome AF: 0.225 AC: 34027 AN: 151478 Hom.: 3818 Cov.: 31 AF XY: 0.224 AC XY: 16575 AN XY: 73958

African (AFR) AF: 0.254 AC: 10475 AN: 41216

American (AMR) AF: 0.257 AC: 3913 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3464

East Asian (EAS) AF: 0.191 AC: 978 AN: 5126

South Asian (SAS) AF: 0.212 AC: 1012 AN: 4764

European-Finnish (FIN) AF: 0.205 AC: 2157 AN: 10514

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14275 AN: 67856

Other (OTH) AF: 0.189 AC: 396 AN: 2094

Alfa AF: 0.215 Hom.: 632

Bravo AF: 0.233

Asia WGS AF: 0.197 AC: 688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 07, 2013

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

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	-0.72
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2304689; hg19: chr7-45103481; COSMIC: COSV51847240; COSMIC: COSV51847240;