rs2229139

chr19-38444640-A-G

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.594A>G(p.Leu198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,612,584 control chromosomes in the GnomAD database, including 316,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28245 hom., cov: 29)
  • Exomes 𝑓: 0.63 (288583 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.221

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=-0.58).
• BP6: Variant 19-38444640-A-G is Benign according to our data. Variant chr19-38444640-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38444640-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.594A>G	p.Leu198=	synonymous_variant	7/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.594A>G	p.Leu198=	synonymous_variant	7/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.594A>G	p.Leu198=	synonymous_variant	7/105	1		P4
RYR1	ENST00000599547.6	c.594A>G	p.Leu198=	synonymous_variant, NMD_transcript_variant	7/80	2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91574 AN: 151362 Hom.: 28238 Cov.: 29

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.624

GnomAD3 exomes AF: 0.609 AC: 152434 AN: 250168 Hom.: 47428 AF XY: 0.602 AC XY: 81451 AN XY: 135282

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.404

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.625 AC: 913320 AN: 1461106 Hom.: 288583 Cov.: 51 AF XY: 0.619 AC XY: 449792 AN XY: 726880

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.678

Gnomad4 ASJ exome AF: 0.606

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.645

Gnomad4 NFE exome AF: 0.641

Gnomad4 OTH exome AF: 0.624

GnomAD4 genome AF: 0.605 AC: 91614 AN: 151478 Hom.: 28245 Cov.: 29 AF XY: 0.600 AC XY: 44400 AN XY: 73964

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.403

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.618

Alfa AF: 0.623 Hom.: 15676

Bravo AF: 0.609

Asia WGS AF: 0.454 AC: 1580 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely 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, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu198Leu in exon 7 of RYR1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 47.6% (2096/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229139). -
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	-	- -

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	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

- -

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	-0.58
Cadd	Benign	12
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2229139; hg19: chr19-38935280; COSMIC: COSV62103826;