rs2960340

Positions:

• chr19-38504798-T-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.8118T>C​(p.Ile2706Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,613,646 control chromosomes in the GnomAD database, including 68,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9226 hom., cov: 31)
  • Exomes 𝑓: 0.28 (59644 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: -2.51

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=-0.62).
• BP6: Variant 19-38504798-T-C is Benign according to our data. Variant chr19-38504798-T-C is described in ClinVar as [Benign]. Clinvar id is 93297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38504798-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8118T>C	p.Ile2706Ile	synonymous_variant	51/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8118T>C	p.Ile2706Ile	synonymous_variant	51/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8118T>C	p.Ile2706Ile	synonymous_variant	51/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1569T>C		non_coding_transcript_exon_variant	12/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8118T>C		non_coding_transcript_exon_variant	51/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50734 AN: 151728 Hom.: 9184 Cov.: 31

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.325 AC: 81577 AN: 251338 Hom.: 14284 AF XY: 0.324 AC XY: 43972 AN XY: 135862

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.277 AC: 405127 AN: 1461800 Hom.: 59644 Cov.: 48 AF XY: 0.282 AC XY: 204732 AN XY: 727212

Gnomad4 AFR exome AF: 0.464

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.335 AC: 50835 AN: 151846 Hom.: 9226 Cov.: 31 AF XY: 0.341 AC XY: 25328 AN XY: 74180

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.345

Alfa AF: 0.274 Hom.: 3971

Bravo AF: 0.343

Asia WGS AF: 0.491 AC: 1704 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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ile2706Ile in exon 51 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 rs2960340). -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:1 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	-	- -
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: 47.003% 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. -

Congenital multicore myopathy with external ophthalmoplegia 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	- -

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	Jun 14, 2016	- -

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

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.34
DANN	Benign	0.51

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: rs2960340; hg19: chr19-38995438; COSMIC: COSV62092623;