rs2915952

chr19-38505335-G-Achr19-38505335-G-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.8337G>A(p.Glu2779=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,608,310 control chromosomes in the GnomAD database, including 67,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8646 hom., cov: 31)
  • Exomes 𝑓: 0.27 (58440 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:17 O:1
• Conservation: PhyloP100: 1.45

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-38505335-G-A is Benign according to our data. Variant chr19-38505335-G-A is described in ClinVar as [Benign]. Clinvar id is 93299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38505335-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8337G>A	p.Glu2779=	synonymous_variant	53/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8337G>A	p.Glu2779=	synonymous_variant	53/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8337G>A	p.Glu2779=	synonymous_variant	53/105	1		P4
RYR1	ENST00000594335.5	c.1791G>A	p.Glu597=	synonymous_variant, NMD_transcript_variant	14/49	1
RYR1	ENST00000599547.6	c.8337G>A	p.Glu2779=	synonymous_variant, NMD_transcript_variant	53/80	2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49470 AN: 151860 Hom.: 8610 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.319 AC: 78977 AN: 247926 Hom.: 13437 AF XY: 0.318 AC XY: 42662 AN XY: 134026

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.275 AC: 400045 AN: 1456332 Hom.: 58440 Cov.: 34 AF XY: 0.279 AC XY: 202266 AN XY: 724460

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.446

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.326 AC: 49567 AN: 151978 Hom.: 8646 Cov.: 31 AF XY: 0.333 AC XY: 24766 AN XY: 74280

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.338

Alfa AF: 0.272 Hom.: 3299

Bravo AF: 0.333

Asia WGS AF: 0.486 AC: 1689 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Glu2779Glu in exon 53 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 42.7% (1879/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2915952). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 46.041% 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. -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Central core myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2019	- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	4.6
Dann	Benign	0.52

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: rs2915952; hg19: chr19-38995975; COSMIC: COSV62092747;