Variant rs200013680 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001035.3(RYR2):c.11126A>T(p.Glu3709Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,416,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E3709E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.76

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. GenCC has associacion of the gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.11126A>T	p.Glu3709Val	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 link	c.11126A>T	p.Glu3709Val	missense_variant	80/105	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.1 link	c.932A>T	p.Glu311Val	missense_variant	11/12			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.*2161A>T		non_coding_transcript_exon_variant	78/104	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000609119.2 link	n.*2161A>T		3_prime_UTR_variant	78/104	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.06e-7

AC:

AN:

1416590

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701220

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:

9.21e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.90

D;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.66

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.016

D;.

Polyphen

0.93

P;.

Vest4

0.51

MutPred

0.18

Gain of helix (P = 0.0496);.;

MVP

0.92

MPC

1.1

ClinPred

0.99

GERP RS

5.9

Varity_R

0.44

gMVP

0.36

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