rs1468571

Positions:

• chr19-38578001-A-C
• chr19-38578001-A-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.14256A>C​(p.Thr4752=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.046 in 1,613,922 control chromosomes in the GnomAD database, including 5,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2016 hom., cov: 31)
  • Exomes 𝑓: 0.039 (3295 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -2.17

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=-0.98).
• BP6: Variant 19-38578001-A-C is Benign according to our data. Variant chr19-38578001-A-C is described in ClinVar as [Benign]. Clinvar id is 93254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38578001-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14256A>C	p.Thr4752=	synonymous_variant	98/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14256A>C	p.Thr4752=	synonymous_variant	98/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17078 AN: 151952 Hom.: 1989 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0733

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0937

GnomAD3 exomes AF: 0.0741 AC: 18620 AN: 251260 Hom.: 1566 AF XY: 0.0649 AC XY: 8818 AN XY: 135858

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.0981

Gnomad SAS exome AF: 0.0664

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0519

GnomAD4 exome AF: 0.0391 AC: 57126 AN: 1461854 Hom.: 3295 Cov.: 32 AF XY: 0.0384 AC XY: 27924 AN XY: 727238

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0649

Gnomad4 FIN exome AF: 0.0485

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0562

GnomAD4 genome AF: 0.113 AC: 17162 AN: 152068 Hom.: 2016 Cov.: 31 AF XY: 0.114 AC XY: 8490 AN XY: 74358

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.0735

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0355 Hom.: 481

Bravo AF: 0.129

Asia WGS AF: 0.111 AC: 384 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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)	Jul 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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. -

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	Aug 17, 2022	- -

not provided Benign:1 Other:1

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

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. -

Central core myopathy Benign:1

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.051
DANN	Benign	0.46

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: rs1468571; hg19: chr19-39068641; COSMIC: COSV62089256;