rs397516548

Positions:

chr1-237640898-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001035.3(RYR2):c.7117G>T(p.Asp2373Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,459,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense, splice_region

Scores

Splicing: ADA: 0.002009

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.71

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 -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.

BP4

Computational evidence support a benign effect (MetaRNN=0.33555442).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105	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.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 linkuse as main transcript	n.7117G>T		splice_region_variant, non_coding_transcript_exon_variant	47/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 linkuse as main transcript	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/106			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 linkuse as main transcript	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246646

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133578

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459674

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725856

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

The Asp2373Tyr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. Additional information is ne eded to fully assess the clinical signficance of this variant. -

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 09, 2024

This missense variant replaces aspartic acid with tyrosine at codon 2373 of the RYR2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/246646 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 28, 2022

This missense variant replaces aspartic acid with tyrosine at codon 2373 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 2/246646 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. -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2373 of the RYR2 protein (p.Asp2373Tyr). This variant is present in population databases (rs397516548, gnomAD 0.002%). 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: 43822). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

Jan 21, 2022

The c.7117G>T (p.D2373Y) alteration is located in exon 47 (coding exon 47) of the RYR2 gene. This alteration results from a G to T substitution at nucleotide position 7117, causing the aspartic acid (D) at amino acid position 2373 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Uncertain

0.42

T;T

Eigen

Benign

-0.069

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.51

Sift

Benign

0.24

T;.

Polyphen

0.020

B;.

Vest4

0.45

MutPred

0.28

Gain of phosphorylation at D2373 (P = 0.0065);.;

MVP

0.90

MPC

0.44

ClinPred

0.15

GERP RS

5.8

Varity_R

0.21

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0020

SpliceAI score (max)

0.030

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