rs199638420

Positions:

chr15-33630030-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000634891.2(RYR3):c.2770A>G(p.Thr924Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,589,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

RYR3
ENST00000634891.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.80

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015210718).

BP6

Variant 15-33630030-A-G is Benign according to our data. Variant chr15-33630030-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461897.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.2770A>G	p.Thr924Ala	missense_variant	22/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.2770A>G	p.Thr924Ala	missense_variant	22/104	1	NM_001036.6	ENSP00000489262	P4	Q15413-1
RYR3	ENST00000389232.9 linkuse as main transcript	c.2770A>G	p.Thr924Ala	missense_variant	22/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7 linkuse as main transcript	c.2770A>G	p.Thr924Ala	missense_variant	22/103	2		ENSP00000399610	A2	Q15413-2
RYR3	ENST00000634418.1 linkuse as main transcript	c.2770A>G	p.Thr924Ala	missense_variant	22/102	5		ENSP00000489529

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000635

AC:

142

AN:

223724

Hom.:

AF XY:

0.000675

AC XY:

AN XY:

119978

show subpopulations

Gnomad AFR exome

AF:

0.000291

Gnomad AMR exome

AF:

0.000888

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000146

Gnomad NFE exome

AF:

0.000499

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.000448

AC:

644

AN:

1437598

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

334

AN XY:

713994

show subpopulations

Gnomad4 AFR exome

AF:

0.000393

Gnomad4 AMR exome

AF:

0.000849

Gnomad4 ASJ exome

AF:

0.00607

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.000227

Gnomad4 NFE exome

AF:

0.000314

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000597

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000710

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000367

AC:

ExAC

AF:

0.000456

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.2770A>G (p.T924A) alteration is located in exon 22 (coding exon 22) of the RYR3 gene. This alteration results from a A to G substitution at nucleotide position 2770, causing the threonine (T) at amino acid position 924 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

RYR3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2021

This variant is classified as likely 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

0.071

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.33

T;.;.;.;.

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.77

T;T;T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.015

T;T;T;T;T

MetaSVM

Uncertain

-0.057

MutationAssessor

Benign

1.4

L;L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.2

.;N;N;.;.

REVEL

Uncertain

0.46

Sift

Benign

0.93

.;T;T;.;.

Polyphen

0.27

B;P;.;.;.

Vest4

0.41

MVP

0.83

MPC

0.25

ClinPred

0.048

GERP RS

5.3

Varity_R

0.32

gMVP

0.31

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