rs370057029

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001035.3(RYR2):c.1144G>A(p.Val382Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,595,420 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 7.86

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 -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.37545842).

BP6

Variant 1-237441457-G-A is Benign according to our data. Variant chr1-237441457-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.1144G>A	p.Val382Met	missense_variant	13/105	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.1144G>A	p.Val382Met	missense_variant	13/105	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.1144G>A	p.Val382Met	missense_variant	13/106			ENSP00000499787
RYR2	ENST00000659194.3 linkuse as main transcript	c.1144G>A	p.Val382Met	missense_variant	13/105			ENSP00000499653
RYR2	ENST00000609119.2 linkuse as main transcript	c.1144G>A	p.Val382Met	missense_variant, NMD_transcript_variant	13/104	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000787

AC:

AN:

241388

Hom.:

AF XY:

0.0000764

AC XY:

AN XY:

130910

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.0000611

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000343

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

196

AN:

1443222

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

716836

show subpopulations

Gnomad4 AFR exome

AF:

0.0000909

Gnomad4 AMR exome

AF:

0.0000685

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0000971

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000120

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000911

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 17, 2015	- -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 21/272778 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

Apr 10, 2023

Arrhythmogenic right ventricular dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 28, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The p.V382M variant (also known as c.1144G>A), located in coding exon 13 of the RYR2 gene, results from a G to A substitution at nucleotide position 1144. The valine at codon 382 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 26, 2024

Variant summary: RYR2 c.1144G>A (p.Val382Met) results in a conservative amino acid change located in the MIR motif (IPR016093) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 1595420 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1144G>A has been reported in the literature in individuals affected with Arrythmia without evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 201209). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.082

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.17

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.050

D;.

Polyphen

0.99

D;.

Vest4

0.51

MVP

0.70

MPC

0.70

ClinPred

0.41

GERP RS

5.3

Varity_R

0.092

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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