rs764823480

Positions:

chr15-33581584-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001036.6(RYR3):c.1514C>T(p.Ala505Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Variant links:

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.115379155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.1514C>T	p.Ala505Val	missense_variant	14/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.1514C>T	p.Ala505Val	missense_variant	14/104	1	NM_001036.6	P4	Q15413-1
RYR3	ENST00000389232.9 linkuse as main transcript	c.1514C>T	p.Ala505Val	missense_variant	14/104	5		A1
RYR3	ENST00000415757.7 linkuse as main transcript	c.1514C>T	p.Ala505Val	missense_variant	14/103	2		A2	Q15413-2
RYR3	ENST00000634418.1 linkuse as main transcript	c.1514C>T	p.Ala505Val	missense_variant	14/102	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

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

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249024

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135086

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726950

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 461884). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (rs764823480, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 505 of the RYR3 protein (p.Ala505Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.78

D;.;.;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.63

N;N;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

.;N;N;.;.

REVEL

Benign

0.20

Sift

Benign

0.30

.;T;T;.;.

Polyphen

0.020

B;B;.;.;.

Vest4

0.18

MutPred

0.52

Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);

MVP

0.43

MPC

0.18

ClinPred

0.053

GERP RS

1.3

Varity_R

0.044

gMVP

0.52

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