rs369152386

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_001035.3(RYR2):c.7099G>A(p.Gly2367Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,612,902 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G2367G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.11

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 -13 ACMG points.

PP2

Missense variant where missense usually causes diseases, RYR2

BP4

Computational evidence support a benign effect (MetaRNN=0.07768881).

BP6

Variant 1-237639185-G-A is Benign according to our data. Variant chr1-237639185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 519433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237639185-G-A is described in Lovd as [Likely_benign]. Variant chr1-237639185-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.7099G>A	p.Gly2367Arg	missense_variant	46/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.7099G>A	p.Gly2367Arg	missense_variant	46/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.7099G>A	p.Gly2367Arg	missense_variant	46/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.7099G>A	p.Gly2367Arg	missense_variant	46/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.7099G>A	p.Gly2367Arg	missense_variant, NMD_transcript_variant	46/104	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248284

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000119

AC:

174

AN:

1460778

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.0000918

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000576

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 17, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

This variant is associated with the following publications: (PMID: 31402444, 31043699, 29032884, 17956252, 22222782, 25041964, 26350513) -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

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

0.085

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Uncertain

0.040

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.078

T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.43

N;.

REVEL

Uncertain

0.47

Sift

Benign

0.083

T;.

Polyphen

0.93

P;.

Vest4

0.57

MutPred

0.21

Gain of solvent accessibility (P = 0.019);.;

MVP

0.51

MPC

0.47

ClinPred

0.096

GERP RS

5.3

Varity_R

0.12

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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