rs200121281

Positions:

chr1-237500896-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_001035.3(RYR2):c.2389G>A(p.Gly797Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 9.99

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 Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

BP6

Variant 1-237500896-G-A is Benign according to our data. Variant chr1-237500896-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180488.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.2389G>A	p.Gly797Arg	missense_variant	21/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.2389G>A	p.Gly797Arg	missense_variant	21/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.2389G>A	p.Gly797Arg	missense_variant	21/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.2389G>A	p.Gly797Arg	missense_variant	21/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.2389G>A	p.Gly797Arg	missense_variant, NMD_transcript_variant	21/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249252

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.000840

Gnomad AMR exome

AF:

0.000174

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000177

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000590

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:

0.00

Alfa

AF:

0.0000145

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2017	Variant summary: The RYR2 c.2389G>A (p.Gly797Arg) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 7/120662 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000715 (7/9794). This frequency is about 29 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance, without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

This missense variant replaces glycine with arginine at codon 797 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 23/280660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 14, 2023

Long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 25, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The p.G797R variant (also known as c.2389G>A), located in coding exon 21 of the RYR2 gene, results from a G to A substitution at nucleotide position 2389. The glycine at codon 797 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.5

D;.

REVEL

Uncertain

0.60

Sift

Benign

0.17

T;.

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.70

Gain of MoRF binding (P = 0.0065);.;

MVP

0.85

MPC

1.3

ClinPred

0.76

GERP RS

6.0

Varity_R

0.62

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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