19-38502916-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.7872C>T(p.Arg2624Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,611,386 control chromosomes in the GnomAD database, including 16,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2624R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.17 ( 2709 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13680 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: -1.22

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 19-38502916-C-T is Benign according to our data. Variant chr19-38502916-C-T is described in ClinVar as [Benign]. Clinvar id is 93295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502916-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.22 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.7872C>T	p.Arg2624Arg	synonymous_variant	Exon 49 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.7872C>T	p.Arg2624Arg	synonymous_variant	Exon 49 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.7872C>T	p.Arg2624Arg	synonymous_variant	Exon 49 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 link	n.1323C>T		non_coding_transcript_exon_variant	Exon 10 of 49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 link	n.7872C>T		non_coding_transcript_exon_variant	Exon 49 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25736

AN:

151788

Hom.:

2695

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.0575

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.167

GnomAD3 exomes

AF:

0.149

AC:

37256

AN:

249646

Hom.:

3485

AF XY:

0.144

AC XY:

19462

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.260

Gnomad ASJ exome

AF:

0.0905

Gnomad EAS exome

AF:

0.0459

Gnomad SAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.130

AC:

189622

AN:

1459480

Hom.:

13680

Cov.:

AF XY:

0.130

AC XY:

94368

AN XY:

726146

show subpopulations

Gnomad4 AFR exome

AF:

0.285

Gnomad4 AMR exome

AF:

0.251

Gnomad4 ASJ exome

AF:

0.0938

Gnomad4 EAS exome

AF:

0.0629

Gnomad4 SAS exome

AF:

0.160

Gnomad4 FIN exome

AF:

0.143

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.135

GnomAD4 genome

AF:

0.170

AC:

25789

AN:

151906

Hom.:

2709

Cov.:

AF XY:

0.171

AC XY:

12683

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.283

Gnomad4 AMR

AF:

0.191

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.0574

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.125

Hom.:

866

Bravo

AF:

0.179

Asia WGS

AF:

0.145

AC:

504

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg2624Arg in exon 49 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 27.7% (1219/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1469698). -

Malignant hyperthermia, susceptibility to, 1

Benign:2

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1Other:1

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1-related disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Benign:1

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

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