rs942040362

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001035.3(RYR2):c.11116G>A(p.Asp3706Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000237 in 1,561,314 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3706Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.54

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 -7 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=0.013501734).

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.11116G>A	p.Asp3706Asn	missense_variant	80/105	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.11116G>A	p.Asp3706Asn	missense_variant	80/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.1 linkuse as main transcript	c.922G>A	p.Asp308Asn	missense_variant	11/12			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 linkuse as main transcript	n.*2151G>A		non_coding_transcript_exon_variant	78/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 linkuse as main transcript	n.*2151G>A		3_prime_UTR_variant	78/104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.000166

AC:

AN:

150606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.0242

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000536

AC:

AN:

186494

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

99030

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:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000851

AC:

AN:

1410708

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

697960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000739

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.000166

AC:

AN:

150606

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

73346

show subpopulations

Gnomad4 AFR

AF:

0.0000489

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:

0.0000386

Hom.:

Bravo

AF:

0.000196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

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

May 14, 2024

This missense variant replaces aspartic acid with asparagine at codon 3706 of 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 RYR2-related disorders in the literature. This variant has been identified in 2/217498 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

Mar 13, 2023

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2024

Reported as an incidental finding in a cohort of individuals referred for whole exome sequencing; however, specific clinical information about the individual(s) harboring this variant was not provided (PMID: 28404607); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); This variant is associated with the following publications: (PMID: 28404607, 19926015) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The p.D3706N variant (also known as c.11116G>A), located in coding exon 80 of the RYR2 gene, results from a G to A substitution at nucleotide position 11116. The aspartic acid at codon 3706 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.51

T;.

Polyphen

0.93

P;.

Vest4

0.32

MutPred

0.23

Gain of helix (P = 0.132);.;

MVP

0.94

MPC

1.2

ClinPred

0.46

GERP RS

5.0

Varity_R

0.086

gMVP

0.18

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