Variant rs146838868 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001036.6(RYR3):c.1277A>G(p.Asn426Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,608,642 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 19 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.77

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:

RYR3 (HGNC:):

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069306195).

BP6

Variant 15-33579984-A-G is Benign according to our data. Variant chr15-33579984-A-G is described in ClinVar as [Benign]. Clinvar id is 461855.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.1277A>G	p.Asn426Ser	missense_variant	13/104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.1277A>G	p.Asn426Ser	missense_variant	13/104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00698

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00281

AC:

687

AN:

244072

Hom.:

AF XY:

0.00279

AC XY:

369

AN XY:

132442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00694

Gnomad SAS exome

AF:

0.0000674

Gnomad FIN exome

AF:

0.0214

Gnomad NFE exome

AF:

0.000802

Gnomad OTH exome

AF:

0.00256

GnomAD4 exome

AF:

0.00127

AC:

1852

AN:

1456546

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

902

AN XY:

724252

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0118

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0190

Gnomad4 NFE exome

AF:

0.000265

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00250

AC:

380

AN:

152096

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

276

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00699

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0268

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000756

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000477

AC:

ExAC

AF:

0.00244

AC:

295

Asia WGS

AF:

0.00289

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

- -

RYR3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.35

T;.;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.67

T;T;T;T;T

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.8

L;L;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

.;N;N;.;.

REVEL

Benign

0.23

Sift

Benign

0.20

.;T;T;.;.

Polyphen

0.026

B;P;.;.;.

Vest4

0.093

MVP

0.78

MPC

0.14

ClinPred

0.042

GERP RS

2.9

Varity_R

0.064

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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