rs2071088

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.7527G>A(p.Val2509=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 1,614,000 control chromosomes in the GnomAD database, including 8,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 775 hom., cov: 31)

Exomes 𝑓: 0.098 ( 8066 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 0.262

Variant links:

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-38500903-G-A is Benign according to our data. Variant chr19-38500903-G-A is described in ClinVar as [Benign]. Clinvar id is 93288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38500903-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.262 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7527G>A	p.Val2509=	synonymous_variant	47/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7527G>A	p.Val2509=	synonymous_variant	47/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7527G>A	p.Val2509=	synonymous_variant	47/105	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.981G>A	p.Val327=	synonymous_variant, NMD_transcript_variant	8/49	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.7527G>A	p.Val2509=	synonymous_variant, NMD_transcript_variant	47/80	2

Frequencies

GnomAD3 genomes

AF:

0.0938

AC:

14258

AN:

152076

Hom.:

766

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0842

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0755

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.0424

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0900

Gnomad OTH

AF:

0.0932

GnomAD3 exomes

AF:

0.108

AC:

27056

AN:

251270

Hom.:

1815

AF XY:

0.113

AC XY:

15313

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0869

Gnomad AMR exome

AF:

0.0895

Gnomad ASJ exome

AF:

0.0745

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.0917

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0975

AC:

142554

AN:

1461806

Hom.:

8066

Cov.:

AF XY:

0.101

AC XY:

73385

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0827

Gnomad4 AMR exome

AF:

0.0903

Gnomad4 ASJ exome

AF:

0.0769

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.221

Gnomad4 FIN exome

AF:

0.0473

Gnomad4 NFE exome

AF:

0.0894

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.0939

AC:

14293

AN:

152194

Hom.:

775

Cov.:

AF XY:

0.0949

AC XY:

7064

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0847

Gnomad4 AMR

AF:

0.101

Gnomad4 ASJ

AF:

0.0755

Gnomad4 EAS

AF:

0.163

Gnomad4 SAS

AF:

0.228

Gnomad4 FIN

AF:

0.0424

Gnomad4 NFE

AF:

0.0900

Gnomad4 OTH

AF:

0.0989

Alfa

AF:

0.0875

Hom.:

400

Bravo

AF:

0.0938

Asia WGS

AF:

0.234

AC:

813

AN:

3478

EpiCase

AF:

0.0955

EpiControl

AF:

0.0945

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Val2509Val in exon 47 of RYR1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 9.2% (406/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2071088). -

Congenital multicore myopathy with external ophthalmoplegia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Central core myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Malignant hyperthermia, susceptibility to, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-Related Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

King Denborough syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

2.3

Dann

Benign

0.69

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