rs4724344

Positions:

• chr7-45012753-T-C
• chr7-45012753-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031443.4(CCM2):​c.30+12390T>C 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 151,606 control chromosomes in the GnomAD database, including 57,327 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 (57327 hom., cov: 26)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• 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/exons	MANE	Protein	UniProt
CCM2	NM_031443.4	c.30+12390T>C		intron_variant		ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.30+12390T>C		intron_variant		1	NM_031443.4	ENSP00000258781	P1

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131363 AN: 151488 Hom.: 57269 Cov.: 26

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.857

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: 131482 AN: 151606 Hom.: 57327 Cov.: 26 AF XY: 0.870 AC XY: 64395 AN XY: 74030

Gnomad4 AFR AF: 0.963

Gnomad4 AMR AF: 0.828

Gnomad4 ASJ AF: 0.776

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.879

Gnomad4 NFE AF: 0.819

Gnomad4 OTH AF: 0.824

Alfa AF: 0.840 Hom.: 6700

Bravo AF: 0.872

Asia WGS AF: 0.860 AC: 2993 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.88
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4724344; hg19: chr7-45052352; COSMIC: COSV51849429;