rs2228069

Variant names:

• chr19-38466163-G-A
• rs2228069
• NM_000540.3:c.2943G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38466163-G-A
• chr19-38466163-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.2943G>A​(p.Thr981Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,612,930 control chromosomes in the GnomAD database, including 293,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27393 hom., cov: 32)
  • Exomes 𝑓: 0.60 (266182 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: -3.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-38466163-G-A is Benign according to our data. Variant chr19-38466163-G-A is described in ClinVar as [Benign]. Clinvar id is 93261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38466163-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.2943G>A	p.Thr981Thr	synonymous_variant	Exon 24 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.2943G>A	p.Thr981Thr	synonymous_variant	Exon 24 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.2943G>A	p.Thr981Thr	synonymous_variant	Exon 24 of 105	1		ENSP00000347667.3
RYR1	ENST00000594111.1	n.36G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
RYR1	ENST00000599547.6	n.2943G>A		non_coding_transcript_exon_variant	Exon 24 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90855 AN: 151958 Hom.: 27381 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.616

GnomAD3 exomes AF: 0.594 AC: 146801 AN: 247338 Hom.: 44301 AF XY: 0.587 AC XY: 78759 AN XY: 134124

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.684

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.545

Gnomad SAS exome AF: 0.438

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.601 AC: 878139 AN: 1460854 Hom.: 266182 Cov.: 68 AF XY: 0.597 AC XY: 433723 AN XY: 726798

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.643

Gnomad4 EAS exome AF: 0.591

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.610

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.598 AC: 90902 AN: 152076 Hom.: 27393 Cov.: 32 AF XY: 0.593 AC XY: 44094 AN XY: 74320

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.667

Gnomad4 ASJ AF: 0.650

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.617

Gnomad4 OTH AF: 0.611

Alfa AF: 0.618 Hom.: 21299

Bravo AF: 0.608

Asia WGS AF: 0.448 AC: 1559 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.632

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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.Thr981Thr in exon 24 of RYR1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 44.0% (1938/4400) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2228069). -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2014

Eurofins Ntd Llc (ga)

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 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

Nov 07, 2021

Genome-Nilou Lab

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. -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Aug 11, 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	-0.70
CADD	Benign	0.073
DANN	Benign	0.80

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: rs2228069; hg19: chr19-38956803; COSMIC: COSV62092589;