rs12973632

Positions:

• chr19-38499953-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.7260C>T​(p.His2420His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,614,042 control chromosomes in the GnomAD database, including 1,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (91 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1139 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: -0.399

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=-0.34).
• BP6: Variant 19-38499953-C-T is Benign according to our data. Variant chr19-38499953-C-T is described in ClinVar as [Benign]. Clinvar id is 133191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38499953-C-T is described in Lovd as [Likely_benign]. Variant chr19-38499953-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.399 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7260C>T	p.His2420His	synonymous_variant	45/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7260C>T	p.His2420His	synonymous_variant	45/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7260C>T	p.His2420His	synonymous_variant	45/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.711C>T		non_coding_transcript_exon_variant	6/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7260C>T		non_coding_transcript_exon_variant	45/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4529 AN: 152122 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0350 AC: 8806 AN: 251386 Hom.: 256 AF XY: 0.0336 AC XY: 4569 AN XY: 135878

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.0903

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0368

GnomAD4 exome AF: 0.0358 AC: 52396 AN: 1461802 Hom.: 1139 Cov.: 37 AF XY: 0.0354 AC XY: 25716 AN XY: 727196

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.0824

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0210

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0378

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0298 AC: 4543 AN: 152240 Hom.: 91 Cov.: 32 AF XY: 0.0281 AC XY: 2092 AN XY: 74428

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.0476

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0307 Hom.: 51

Bravo AF: 0.0336

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2015	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His2420His in exon 45 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 3.3% (287/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12973632). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

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

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

Jun 14, 2016

- -

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

Aug 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.0
DANN	Benign	0.49

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: rs12973632; hg19: chr19-38990593;