1-237511754-C-T

Position:

chr1-237511754-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The NM_001035.3(RYR2):c.2785C>T(p.Arg929Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,549,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R929G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.55

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:

RYR2 (HGNC:):

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.2785C>T	p.Arg929Cys	missense_variant	24/105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.2785C>T	p.Arg929Cys	missense_variant	24/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 linkuse as main transcript	n.2785C>T		non_coding_transcript_exon_variant	24/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 linkuse as main transcript	c.2785C>T	p.Arg929Cys	missense_variant	24/106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 linkuse as main transcript	c.2785C>T	p.Arg929Cys	missense_variant	24/105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

146932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000500

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000519

AC:

AN:

192794

Hom.:

AF XY:

0.00000976

AC XY:

AN XY:

102504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1402712

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

693734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000186

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000136

AC:

AN:

146932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70882

show subpopulations

Gnomad4 AFR

AF:

0.0000500

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000354

Hom.:

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 16, 2024

This missense variant replaces arginine with cysteine at codon 929 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 1/192794 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

Nov 06, 2022

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 929 of the RYR2 protein (p.Arg929Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2074093). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The p.R929C variant (also known as c.2785C>T), located in coding exon 24 of the RYR2 gene, results from a C to T substitution at nucleotide position 2785. The arginine at codon 929 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.47

MVP

0.84

MPC

1.3

ClinPred

1.0

GERP RS

4.6

Varity_R

0.58

gMVP

0.78

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