7-45019513-G-T

Variant names:

• chr7-45019513-G-T
• rs4724347
• NM_031443.4:c.31-18740G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031443.4(CCM2):​c.31-18740G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 152,158 control chromosomes in the GnomAD database, including 57,539 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (57539 hom., cov: 30)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCM2	NM_031443.4	c.31-18740G>T		intron_variant	Intron 1 of 9	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.31-18740G>T		intron_variant	Intron 1 of 9	1	NM_031443.4	ENSP00000258781.7

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131835 AN: 152038 Hom.: 57481 Cov.: 30

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.824

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.867 AC: 131955 AN: 152158 Hom.: 57539 Cov.: 30 AF XY: 0.870 AC XY: 64693 AN XY: 74394

African (AFR) AF: 0.963 AC: 40017 AN: 41538

American (AMR) AF: 0.826 AC: 12622 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2693 AN: 3472

East Asian (EAS) AF: 0.910 AC: 4701 AN: 5168

South Asian (SAS) AF: 0.858 AC: 4135 AN: 4818

European-Finnish (FIN) AF: 0.879 AC: 9303 AN: 10588

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.819 AC: 55699 AN: 67978

Other (OTH) AF: 0.824 AC: 1737 AN: 2108

Alfa AF: 0.837 Hom.: 6247

Bravo AF: 0.872

Asia WGS AF: 0.862 AC: 2999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.34
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4724347; hg19: chr7-45059112;