7-45000464-G-T

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.30+101G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.085 in 187,022 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (304 hom., cov: 14)
  • Exomes 𝑓: 0.13 (281 hom.)
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.32

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=-0.8).
• BP6: Variant 7-45000464-G-T is Benign according to our data. Variant chr7-45000464-G-T is described in ClinVar as [Benign]. Clinvar id is 1291962.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.30+101G>T		intron_variant		ENST00000258781.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 5383 AN: 103608 Hom.: 304 Cov.: 14

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0520

Gnomad ASJ AF: 0.0774

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0607

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0552

GnomAD4 exome AF: 0.126 AC: 10510 AN: 83380 Hom.: 281 AF XY: 0.126 AC XY: 5359 AN XY: 42442

Gnomad4 AFR exome AF: 0.0415

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.0904

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.0519 AC: 5381 AN: 103642 Hom.: 304 Cov.: 14 AF XY: 0.0527 AC XY: 2577 AN XY: 48938

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.0521

Gnomad4 ASJ AF: 0.0774

Gnomad4 EAS AF: 0.00389

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.0691

Gnomad4 OTH AF: 0.0554

Alfa AF: 0.0237 Hom.: 43

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.1
Dann	Benign	0.84
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		3.3

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: rs186517708; hg19: chr7-45040063;