rs199693714

chr1-237441448-G-Achr1-237441448-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):c.1135G>A(p.Val379Met) variant causes a missense change. The variant allele was found at a frequency of 0.000194 in 1,598,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.14

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.019839793).
• BP6: Variant 1-237441448-G-A is Benign according to our data. Variant chr1-237441448-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237441448-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000992 (151/152262) while in subpopulation AFR AF= 0.00332 (138/41560). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.1135G>A	p.Val379Met	missense_variant	13/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.1135G>A	p.Val379Met	missense_variant	13/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.1135G>A	p.Val379Met	missense_variant	13/106
RYR2	ENST00000659194.3	c.1135G>A	p.Val379Met	missense_variant	13/105
RYR2	ENST00000609119.2	c.1135G>A	p.Val379Met	missense_variant, NMD_transcript_variant	13/104	5

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000215 AC: 52 AN: 242258 Hom.: 0 AF XY: 0.000129 AC XY: 17 AN XY: 131360

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 159 AN: 1445942 Hom.: 0 Cov.: 31 AF XY: 0.0000891 AC XY: 64 AN XY: 718364

Gnomad4 AFR exome AF: 0.00351

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.0000362

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.000268

GnomAD4 genome AF: 0.000992 AC: 151 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74438

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00215 AC: 8

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000257 AC: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2016	Variant summary: The c.1135G>A variant affects a conserved nucleotide and results in a replacement of a Valine (V) with a Methionine (M). Both residues are medium size and hydrophobic, therefore this Valine to Methionine substitution likely does not alter the physico-chemical properties of the RYR2 protein. 2/4 in silico tools predict the variant to be benign. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.026% which exceeds the maximal expected allele frequency of a disease causing RYR2 allele (0.01%). Additionally, in the African ExAC subcohort, the observed allele frequency is 0.28% which further supports a neutral impact. To our knowledge, the variant has not been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Considering all evidence, the variant is classified as Likely Benign until more information becomes available. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 23, 2015	p.Val379Met in exon 13 of RYR2: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence. It h as been identified in 0.3% (27/9794) of African chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199693714). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 02, 2018

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.89	N;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.020	D;.
Polyphen		0.70	P;.
Vest4		0.28
MVP		0.62
MPC		0.54
ClinPred		0.025	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.27

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: rs199693714; hg19: chr1-237604748; COSMIC: COSV63721844;