rs3745847

chr19-38459264-C-T

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.2286C>T(p.Pro762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,613,638 control chromosomes in the GnomAD database, including 332,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30087 hom., cov: 30)
  • Exomes 𝑓: 0.64 (302170 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -7.84

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=-0.69).
• BP6: Variant 19-38459264-C-T is Benign according to our data. Variant chr19-38459264-C-T is described in ClinVar as [Benign]. Clinvar id is 93259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38459264-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2286C>T	p.Pro762=	synonymous_variant	19/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2286C>T	p.Pro762=	synonymous_variant	19/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2286C>T	p.Pro762=	synonymous_variant	19/105	1		P4
RYR1	ENST00000599547.6	c.2286C>T	p.Pro762=	synonymous_variant, NMD_transcript_variant	19/80	2

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94620 AN: 151752 Hom.: 30074 Cov.: 30

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.627 AC: 157507 AN: 251350 Hom.: 50391 AF XY: 0.619 AC XY: 84129 AN XY: 135852

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.604

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.640 AC: 935058 AN: 1461768 Hom.: 302170 Cov.: 57 AF XY: 0.634 AC XY: 460975 AN XY: 727198

Gnomad4 AFR exome AF: 0.532

Gnomad4 AMR exome AF: 0.687

Gnomad4 ASJ exome AF: 0.665

Gnomad4 EAS exome AF: 0.647

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.693

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.623 AC: 94669 AN: 151870 Hom.: 30087 Cov.: 30 AF XY: 0.620 AC XY: 46027 AN XY: 74230

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.689

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.708

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.629

Alfa AF: 0.654 Hom.: 45389

Bravo AF: 0.624

Asia WGS AF: 0.452 AC: 1574 AN: 3478

EpiCase AF: 0.662

EpiControl AF: 0.670

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
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, 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.Pro762Pro in exon 19 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 46.3% (2039/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3745847). -
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+	-	- -

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	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	- -

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 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. -

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

Aug 11, 2021

- -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.49
Dann	Benign	0.78

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: rs3745847; hg19: chr19-38949904; COSMIC: COSV62092585;