rs73694268

Positions:

• chr7-45064558-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000258781.11(CCM2):​c.384G>A​(p.Glu128=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,018 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (23 hom.)
• Consequence: CCM2 ENST00000258781.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.278

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-45064558-G-A is Benign according to our data. Variant chr7-45064558-G-A is described in ClinVar as [Benign]. Clinvar id is 261972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.278 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1570/152294) while in subpopulation AFR AF= 0.0365 (1515/41528). AF 95% confidence interval is 0.035. There are 25 homozygotes in gnomad4. There are 745 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1570 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCM2	NM_031443.4	c.384G>A	p.Glu128=	synonymous_variant	4/10	ENST00000258781.11	NP_113631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCM2	ENST00000258781.11	c.384G>A	p.Glu128=	synonymous_variant	4/10	1	NM_031443.4	ENSP00000258781	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1565 AN: 152176 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00256 AC: 643 AN: 251228 Hom.: 3 AF XY: 0.00193 AC XY: 262 AN XY: 135832

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1461724 Hom.: 23 Cov.: 33 AF XY: 0.000908 AC XY: 660 AN XY: 727168

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.0103 AC: 1570 AN: 152294 Hom.: 25 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74478

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00521 Hom.: 5

Bravo AF: 0.0112

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cerebral cavernous malformation 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 23, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs73694268; hg19: chr7-45104157;