1-237417111-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP2PP3BP6

The NM_001035.3(RYR2):c.836C>A(p.Thr279Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 152,046 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T279M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.98

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular dysplasia 2
Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
catecholaminergic polymorphic ventricular tachycardia 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001035.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

BP6

Variant 1-237417111-C-A is Benign according to our data. Variant chr1-237417111-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1171104.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.836C>A	p.Thr279Lys	missense_variant	Exon 11 of 105	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.836C>A	p.Thr279Lys	missense_variant	Exon 11 of 105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.2 link	c.836C>A	p.Thr279Lys	missense_variant	Exon 11 of 106			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.836C>A		non_coding_transcript_exon_variant	Exon 11 of 104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726830

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111214

Other (OTH)

AF:

0.00

AC:

AN:

60354

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces threonine with lysine at codon 279 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 cardiovascular disorders in the literature. This variant has been identified in 1/31382 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

Aug 25, 2020

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Aug 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.7

L;.

PhyloP100

5.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;.

REVEL

Uncertain

0.55

Sift

Benign

0.071

T;.

Polyphen

0.98

D;.

Vest4

0.76

MutPred

0.66

Gain of helix (P = 0.0854);.;

MVP

0.77

MPC

1.1

ClinPred

0.95

GERP RS

6.0

Varity_R

0.31

gMVP

0.75

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over