rs3766871

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001035.3(RYR2):c.5656G>A(p.Gly1886Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 1,609,148 control chromosomes in the GnomAD database, including 1,711 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1886V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.061 ( 447 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1264 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.45

Variant links:

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]

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.002141565).

BP6

Variant 1-237614784-G-A is Benign according to our data. Variant chr1-237614784-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237614784-G-A is described in Lovd as [Pathogenic]. Variant chr1-237614784-G-A is described in Lovd as [Benign]. Variant chr1-237614784-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.5656G>A	p.Gly1886Ser	missense_variant	37/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.5656G>A	p.Gly1886Ser	missense_variant	37/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.5656G>A	p.Gly1886Ser	missense_variant	37/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.5656G>A	p.Gly1886Ser	missense_variant	37/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.5656G>A	p.Gly1886Ser	missense_variant, NMD_transcript_variant	37/104	5

Frequencies

GnomAD3 genomes

AF:

0.0603

AC:

9178

AN:

152122

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0320

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.0728

Gnomad SAS

AF:

0.0453

Gnomad FIN

AF:

0.0215

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0284

Gnomad OTH

AF:

0.0532

GnomAD3 exomes

AF:

0.0404

AC:

9914

AN:

245230

Hom.:

332

AF XY:

0.0391

AC XY:

5212

AN XY:

133210

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.0813

Gnomad SAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.0245

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0350

AC:

51011

AN:

1456908

Hom.:

1264

Cov.:

AF XY:

0.0351

AC XY:

25385

AN XY:

724032

show subpopulations

Gnomad4 AFR exome

AF:

0.149

Gnomad4 AMR exome

AF:

0.0216

Gnomad4 ASJ exome

AF:

0.0187

Gnomad4 EAS exome

AF:

0.0669

Gnomad4 SAS exome

AF:

0.0418

Gnomad4 FIN exome

AF:

0.0269

Gnomad4 NFE exome

AF:

0.0309

Gnomad4 OTH exome

AF:

0.0414

GnomAD4 genome

AF:

0.0606

AC:

9226

AN:

152240

Hom.:

447

Cov.:

AF XY:

0.0591

AC XY:

4400

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.139

Gnomad4 AMR

AF:

0.0319

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.0722

Gnomad4 SAS

AF:

0.0450

Gnomad4 FIN

AF:

0.0215

Gnomad4 NFE

AF:

0.0284

Gnomad4 OTH

AF:

0.0550

Alfa

AF:

0.0350

Hom.:

333

Bravo

AF:

0.0645

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0363

AC:

140

ESP6500AA

AF:

0.129

AC:

515

ESP6500EA

AF:

0.0311

AC:

259

ExAC

AF:

0.0425

AC:

5144

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

EpiCase

AF:

0.0302

EpiControl

AF:

0.0315

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Nov 11, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -

Cardiomyopathy

Benign:2

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 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: 25773045, 30403697, 27153395, 27663074, 18326664, 19926015, 20408814, 24025405) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.92

N;.

REVEL

Benign

0.094

Sift

Benign

0.34

T;.

Polyphen

0.0020

B;.

Vest4

0.076

MPC

0.36

ClinPred

0.012

GERP RS

4.8

Varity_R

0.10

gMVP

0.071

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over