7-45000464-G-GT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_031443.4(CCM2):c.30+101_30+102insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 189,776 control chromosomes in the GnomAD database, including 18,301 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (9774 hom., cov: 0)
  • Exomes 𝑓: 0.53 (8527 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.570

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 -10 ACMG points.

• BP6: Variant 7-45000464-G-GT is Benign according to our data. Variant chr7-45000464-G-GT is described in ClinVar as [Benign]. Clinvar id is 1222839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.30+101_30+102insT		intron_variant		ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.30+101_30+102insT		intron_variant		1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 41661 AN: 103462 Hom.: 9779 Cov.: 0

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.463

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.527 AC: 45489 AN: 86280 Hom.: 8527 AF XY: 0.525 AC XY: 23056 AN XY: 43930

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.485

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.515

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.402 AC: 41645 AN: 103496 Hom.: 9774 Cov.: 0 AF XY: 0.402 AC XY: 19631 AN XY: 48890

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.708

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.425

Alfa AF: 0.233 Hom.: 645

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs558165400; hg19: chr7-45040063; COSMIC: COSV51848404;