7-45000457-G-GC

Variant summary

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

The NM_031443.4(CCM2):c.30+94_30+95insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 337,280 control chromosomes in the GnomAD database, including 513 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (251 hom., cov: 19)
  • Exomes 𝑓: 0.032 (262 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.188

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 7-45000457-G-GC is Benign according to our data. Variant chr7-45000457-G-GC is described in ClinVar as [Benign]. Clinvar id is 1224029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.30+94_30+95insC		intron_variant		ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.30+94_30+95insC		intron_variant		1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 5064 AN: 121998 Hom.: 251 Cov.: 19

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0661

Gnomad MID AF: 0.0368

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0498

GnomAD4 exome AF: 0.0323 AC: 6943 AN: 215204 Hom.: 262 AF XY: 0.0331 AC XY: 3592 AN XY: 108376

Gnomad4 AFR exome AF: 0.00902

Gnomad4 AMR exome AF: 0.0285

Gnomad4 ASJ exome AF: 0.0521

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.0628

Gnomad4 NFE exome AF: 0.0333

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0415 AC: 5062 AN: 122076 Hom.: 251 Cov.: 19 AF XY: 0.0412 AC XY: 2426 AN XY: 58932

Gnomad4 AFR AF: 0.00950

Gnomad4 AMR AF: 0.0396

Gnomad4 ASJ AF: 0.0715

Gnomad4 EAS AF: 0.00107

Gnomad4 SAS AF: 0.0119

Gnomad4 FIN AF: 0.0661

Gnomad4 NFE AF: 0.0587

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0153 Hom.: 34

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

May 28, 2021

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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: rs1403112546; hg19: chr7-45040056;