rs2229144

Variant names:

• chr19-38504270-G-A
• rs2229144
• NM_000540.3:c.7977G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38504270-G-A
• chr19-38504270-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.7977G>A​(p.Thr2659Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,613,528 control chromosomes in the GnomAD database, including 68,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9214 hom., cov: 31)
  • Exomes 𝑓: 0.28 (59100 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: -5.01
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-38504270-G-A is Benign according to our data. Variant chr19-38504270-G-A is described in ClinVar as Benign. ClinVar VariationId is 93296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7977G>A	p.Thr2659Thr	synonymous_variant	Exon 50 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7977G>A	p.Thr2659Thr	synonymous_variant	Exon 50 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50690 AN: 151704 Hom.: 9172 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.339

GnomAD2 exomes AF: 0.323 AC: 81058 AN: 250988 AF XY: 0.322

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403687 AN: 1461706 Hom.: 59100 Cov.: 38 AF XY: 0.280 AC XY: 203818 AN XY: 727140

African (AFR) AF: 0.464 AC: 15516 AN: 33474

American (AMR) AF: 0.390 AC: 17443 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6844 AN: 26134

East Asian (EAS) AF: 0.338 AC: 13421 AN: 39698

South Asian (SAS) AF: 0.437 AC: 37724 AN: 86240

European-Finnish (FIN) AF: 0.293 AC: 15633 AN: 53406

Middle Eastern (MID) AF: 0.339 AC: 1956 AN: 5766

European-Non Finnish (NFE) AF: 0.249 AC: 277275 AN: 1111894

Other (OTH) AF: 0.296 AC: 17875 AN: 60392

GnomAD4 genome AF: 0.335 AC: 50791 AN: 151822 Hom.: 9214 Cov.: 31 AF XY: 0.341 AC XY: 25302 AN XY: 74180

African (AFR) AF: 0.460 AC: 19045 AN: 41358

American (AMR) AF: 0.358 AC: 5464 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1862 AN: 5150

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4814

European-Finnish (FIN) AF: 0.289 AC: 3045 AN: 10528

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17228 AN: 67952

Other (OTH) AF: 0.344 AC: 723 AN: 2100

Alfa AF: 0.286 Hom.: 6219

Bravo AF: 0.343

Asia WGS AF: 0.485 AC: 1683 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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

- -

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

- -

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.Thr2659Thr in exon 50 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 45.8% (2016/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229144). -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

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: 47.05% in ExAC) 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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

Jan 12, 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

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

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

- -

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	-0.71
CADD	Benign	0.35
DANN	Benign	0.66
PhyloP100		-5.0
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229144; hg19: chr19-38994910; COSMIC: COSV62092617;