Variant 1-237614784-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2PM5PP2BP4_Moderate

The NM_001035.3(RYR2):c.5656G>T(p.Gly1886Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1886S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

RYR2
NM_001035.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.45

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:

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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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-237614784-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, RYR2

BP4

Computational evidence support a benign effect (MetaRNN=0.19668928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.5656G>T	p.Gly1886Cys	missense_variant	37/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.5656G>T	p.Gly1886Cys	missense_variant	37/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.5656G>T	p.Gly1886Cys	missense_variant	37/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.5656G>T	p.Gly1886Cys	missense_variant	37/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.5656G>T	p.Gly1886Cys	missense_variant, NMD_transcript_variant	37/104	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.17

Sift

Uncertain

0.017

D;.

Polyphen

0.46

P;.

Vest4

0.35

MutPred

0.21

Gain of methylation at K1887 (P = 0.0154);.;

MVP

0.42

MPC

0.56

ClinPred

0.48

GERP RS

4.8

Varity_R

0.28

gMVP

0.11

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over