7-45027418-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031443.4(CCM2):c.31-10835A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 517,936 control chromosomes in the GnomAD database, including 186,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.87 (57580 hom., cov: 32)
  • Exomes 𝑓: 0.84 (129353 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.676

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-45027418-A-G is Benign according to our data. Variant chr7-45027418-A-G is described in ClinVar as [Benign]. Clinvar id is 1278177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.31-10835A>G		intron_variant		ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.31-10835A>G		intron_variant		1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131934 AN: 152130 Hom.: 57522 Cov.: 32

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.824

GnomAD4 exome AF: 0.839 AC: 306932 AN: 365688 Hom.: 129353 Cov.: 3 AF XY: 0.838 AC XY: 163429 AN XY: 194940

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.850

Gnomad4 ASJ exome AF: 0.784

Gnomad4 EAS exome AF: 0.923

Gnomad4 SAS exome AF: 0.859

Gnomad4 FIN exome AF: 0.876

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.839

GnomAD4 genome AF: 0.867 AC: 132053 AN: 152248 Hom.: 57580 Cov.: 32 AF XY: 0.870 AC XY: 64744 AN XY: 74440

Gnomad4 AFR AF: 0.963

Gnomad4 AMR AF: 0.826

Gnomad4 ASJ AF: 0.776

Gnomad4 EAS AF: 0.910

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.879

Gnomad4 NFE AF: 0.820

Gnomad4 OTH AF: 0.824

Alfa AF: 0.818 Hom.: 80526

Bravo AF: 0.872

Asia WGS AF: 0.863 AC: 3002 AN: 3478

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 10, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	6.6
Dann	Benign	0.58

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: rs1294962; hg19: chr7-45067017;