rs2304151

chr19-38517363-G-A

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.9690G>A(p.Leu3230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,613,208 control chromosomes in the GnomAD database, including 4,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (394 hom., cov: 31)
  • Exomes 𝑓: 0.073 (4538 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 1.04

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=-0.45).
• BP6: Variant 19-38517363-G-A is Benign according to our data. Variant chr19-38517363-G-A is described in ClinVar as [Benign]. Clinvar id is 93308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38517363-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.9690G>A	p.Leu3230=	synonymous_variant	66/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.9690G>A	p.Leu3230=	synonymous_variant	66/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.9690G>A	p.Leu3230=	synonymous_variant	66/105	1		P4
RYR1	ENST00000594335.5	c.*433G>A		3_prime_UTR_variant, NMD_transcript_variant	26/49	1
RYR1	ENST00000599547.6	c.*449G>A		3_prime_UTR_variant, NMD_transcript_variant	65/80	2

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9540 AN: 152002 Hom.: 393 Cov.: 31

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0756

GnomAD3 exomes AF: 0.0851 AC: 21056 AN: 247386 Hom.: 1054 AF XY: 0.0887 AC XY: 11910 AN XY: 134344

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.0736

Gnomad ASJ exome AF: 0.0806

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.0859

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0734 AC: 107222 AN: 1461088 Hom.: 4538 Cov.: 35 AF XY: 0.0762 AC XY: 55409 AN XY: 726884

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.0707

Gnomad4 ASJ exome AF: 0.0828

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0845

Gnomad4 NFE exome AF: 0.0656

Gnomad4 OTH exome AF: 0.0738

GnomAD4 genome AF: 0.0628 AC: 9546 AN: 152120 Hom.: 394 Cov.: 31 AF XY: 0.0657 AC XY: 4887 AN XY: 74376

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.0930

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0874

Gnomad4 NFE AF: 0.0662

Gnomad4 OTH AF: 0.0772

Alfa AF: 0.0652 Hom.: 235

Bravo AF: 0.0582

Asia WGS AF: 0.143 AC: 494 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu3230Leu in exon 66 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 6.6% (571/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2304151). -

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	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

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

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. -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-Related Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2304151; hg19: chr19-39008003; COSMIC: COSV62101146;