rs41315858

chr1-237614782-G-Achr1-237614782-G-C

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.5654G>A(p.Gly1885Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,609,734 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. G1885A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 32)
  • Exomes 𝑓: 0.024 (512 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.388

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=0.0018713474).
• BP6: Variant 1-237614782-G-A is Benign according to our data. Variant chr1-237614782-G-A is described in ClinVar as [Benign]. Clinvar id is 36746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237614782-G-A is described in Lovd as [Pathogenic]. Variant chr1-237614782-G-A is described in Lovd as [Benign]. Variant chr1-237614782-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2599/152334) while in subpopulation NFE AF= 0.0282 (1921/68024). AF 95% confidence interval is 0.0272. There are 25 homozygotes in gnomad4. There are 1194 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2600 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.5654G>A	p.Gly1885Glu	missense_variant	37/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.5654G>A	p.Gly1885Glu	missense_variant	37/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.5654G>A	p.Gly1885Glu	missense_variant	37/106
RYR2	ENST00000659194.3	c.5654G>A	p.Gly1885Glu	missense_variant	37/105
RYR2	ENST00000609119.2	c.5654G>A	p.Gly1885Glu	missense_variant, NMD_transcript_variant	37/104	5

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2600 AN: 152216 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0156 AC: 3828 AN: 245448 Hom.: 40 AF XY: 0.0154 AC XY: 2057 AN XY: 133354

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.00874

Gnomad ASJ exome AF: 0.00830

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00152

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0239 AC: 34852 AN: 1457400 Hom.: 512 Cov.: 31 AF XY: 0.0232 AC XY: 16835 AN XY: 724356

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.00721

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0289

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0171 AC: 2599 AN: 152334 Hom.: 25 Cov.: 32 AF XY: 0.0160 AC XY: 1194 AN XY: 74484

Gnomad4 AFR AF: 0.00531

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0229 Hom.: 65

Bravo AF: 0.0161

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00526 AC: 21

ESP6500EA AF: 0.0234 AC: 195

ExAC AF: 0.0149 AC: 1803

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0256

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2012	Allele frequency = 2.4% (n=160 alleles), EA cohort, NHLBI ESP. -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30403697, 25925909, 28798025, 28404607, 27153395, 21315846, 19926015, 24025405, 24237251, 18326664) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 11, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 20, 2015

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 10, 2014

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 11, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2015

This alteration is classified as 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	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	4.4
Dann	Benign	0.50
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.55	N;.
REVEL	Benign	0.090
Sift	Benign	0.89	T;.
Polyphen		0.0	B;.
Vest4		0.067
MPC		0.47
ClinPred		0.0052	T
GERP RS		-2.4
Varity_R		0.049
gMVP		0.11

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: rs41315858; hg19: chr1-237778082;