rs2289366

chr7-45073522-G-A

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.866G>A(p.Ser289Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,166 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (382 hom.)
• Consequence: CCM2 NM_031443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.69

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=0.0018657148).
• BP6: Variant 7-45073522-G-A is Benign according to our data. Variant chr7-45073522-G-A is described in ClinVar as [Benign]. Clinvar id is 261974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-45073522-G-A is described in Lovd as [Likely_benign]. Variant chr7-45073522-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCM2	NM_031443.4	c.866G>A	p.Ser289Asn	missense_variant	8/10	ENST00000258781.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCM2	ENST00000258781.11	c.866G>A	p.Ser289Asn	missense_variant	8/10	1	NM_031443.4	P1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152220 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0173 AC: 4320 AN: 250050 Hom.: 302 AF XY: 0.0135 AC XY: 1832 AN XY: 135486

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00680

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.000562

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.00405 AC: 5922 AN: 1460828 Hom.: 382 Cov.: 32 AF XY: 0.00359 AC XY: 2607 AN XY: 726716

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00829

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.000400

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152338 Hom.: 55 Cov.: 33 AF XY: 0.00800 AC XY: 596 AN XY: 74484

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.0623

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00714

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00494 Hom.: 63

Bravo AF: 0.0130

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0130 AC: 1574

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2020	- -

Cerebral cavernous malformation 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28655553) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
MetaRNN	Benign	0.0019	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.074	T;T;T;T;D;T
Sift4G	Uncertain	0.051	T;D;D;D;D;D
Polyphen		0.87	P;.;.;.;.;.
Vest4		0.20
MPC		0.68
ClinPred		0.026	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2289366; hg19: chr7-45113121; COSMIC: COSV51848552; COSMIC: COSV51848552;