rs2229146

Variant names:

• chr19-38506350-T-C
• rs2229146
• NM_000540.3:c.8589T>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.8589T>C (p.Ser2863=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 40732/91032, 9442 homozygotes) of the c.8589T>C variant in RYR1 is 0.4430 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA024932/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.33 (8774 hom., cov: 30)
  • Exomes 𝑓: 0.28 (61178 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:19 O:1
• Conservation: PhyloP100: -2.77

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8589T>C	p.Ser2863Ser	synonymous_variant	Exon 55 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8589T>C	p.Ser2863Ser	synonymous_variant	Exon 55 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8589T>C	p.Ser2863Ser	synonymous_variant	Exon 55 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.2040T>C		non_coding_transcript_exon_variant	Exon 16 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8589T>C		non_coding_transcript_exon_variant	Exon 55 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49936 AN: 151576 Hom.: 8738 Cov.: 30

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.325 AC: 81757 AN: 251438 Hom.: 14246 AF XY: 0.325 AC XY: 44136 AN XY: 135898

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.282 AC: 411856 AN: 1461712 Hom.: 61178 Cov.: 47 AF XY: 0.286 AC XY: 208090 AN XY: 727186

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.330 AC: 50033 AN: 151694 Hom.: 8774 Cov.: 30 AF XY: 0.337 AC XY: 24961 AN XY: 74118

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.339

Alfa AF: 0.276 Hom.: 12085

Bravo AF: 0.336

Asia WGS AF: 0.487 AC: 1692 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.270

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

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.Ser2863Ser in exon 55 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 43.0% (1893/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229146). -

Jan 25, 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. -

not provided Uncertain:1 Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 45.825% in gnomAD_Exomes) based on the frequency threshold of 2.223% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 9 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. A synonymous variant not located in a splice region. -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

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. -

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

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

- -

RYR1-related myopathy Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.8589T>C (p.Ser2863=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 40732/91032, 9442 homozygotes) of the c.8589T>C variant in RYR1 is 0.4430 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

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

- -

King Denborough syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

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

Oct 08, 2021

Fulgent Genetics, Fulgent Genetics

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	-0.69
CADD	Benign	2.6
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2229146; hg19: chr19-38996990; COSMIC: COSV62092503;