rs11552377

chr7-45064532-G-Achr7-45064532-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031443.4(CCM2):c.358G>A(p.Val120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,656 control chromosomes in the GnomAD database, including 22,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V120N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1653 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20872 hom.)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017606616).
• BP6: Variant 7-45064532-G-A is Benign according to our data. Variant chr7-45064532-G-A is described in ClinVar as [Benign]. Clinvar id is 261971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45064532-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.358G>A	p.Val120Ile	missense_variant	4/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.358G>A	p.Val120Ile	missense_variant	4/10	1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20177 AN: 152084 Hom.: 1655 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.147 AC: 36914 AN: 250892 Hom.: 3077 AF XY: 0.152 AC XY: 20652 AN XY: 135632

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0923

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.165 AC: 240505 AN: 1461454 Hom.: 20872 Cov.: 34 AF XY: 0.165 AC XY: 120294 AN XY: 727012

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0777

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.133 AC: 20177 AN: 152202 Hom.: 1653 Cov.: 32 AF XY: 0.130 AC XY: 9673 AN XY: 74416

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.0903

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.175

Alfa AF: 0.174 Hom.: 5324

Bravo AF: 0.128

TwinsUK AF: 0.179 AC: 664

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.184 AC: 1582

ExAC AF: 0.145 AC: 17648

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.193

EpiControl AF: 0.192

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebral cavernous malformation 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28000143, 20419355, 23485406) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.035	T;.;.;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;.;.;.;.
MutationTaster	Benign	0.16	P;P;P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.26	N;N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.86	T;T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T
Polyphen		0.015	B;.;.;.;.;.
Vest4		0.044
MPC		0.25
ClinPred		0.011	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.12

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: rs11552377; hg19: chr7-45104131; COSMIC: COSV51848386; COSMIC: COSV51848386;