rs2228070

Positions:

• chr19-38466199-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.2979C>T​(p.Asn993Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,162 control chromosomes in the GnomAD database, including 45,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3702 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41566 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -4.03

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 19-38466199-C-T is Benign according to our data. Variant chr19-38466199-C-T is described in ClinVar as [Benign]. Clinvar id is 93262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38466199-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.2979C>T	p.Asn993Asn	synonymous_variant	24/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.2979C>T	p.Asn993Asn	synonymous_variant	24/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.2979C>T	p.Asn993Asn	synonymous_variant	24/105	1		ENSP00000347667.3
RYR1	ENST00000594111.1	n.72C>T		non_coding_transcript_exon_variant	1/2	2
RYR1	ENST00000599547.6	n.2979C>T		non_coding_transcript_exon_variant	24/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30970 AN: 152090 Hom.: 3705 Cov.: 32

Gnomad AFR AF: 0.0977

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.242 AC: 60221 AN: 248726 Hom.: 8125 AF XY: 0.244 AC XY: 32956 AN XY: 134822

Gnomad AFR exome AF: 0.0936

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.275

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.234 AC: 341717 AN: 1460952 Hom.: 41566 Cov.: 48 AF XY: 0.235 AC XY: 170733 AN XY: 726868

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.204 AC: 30979 AN: 152210 Hom.: 3702 Cov.: 32 AF XY: 0.212 AC XY: 15767 AN XY: 74418

Gnomad4 AFR AF: 0.0979

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.198

Alfa AF: 0.212 Hom.: 4286

Bravo AF: 0.189

Asia WGS AF: 0.355 AC: 1235 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Asn993Asn 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 22.5% (1934/8596) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2228070). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2014	- -

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 12, 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. -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.83
DANN	Benign	0.88

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: rs2228070; hg19: chr19-38956839; COSMIC: COSV62090015;