19-38490644-A-G

Position:

• chr19-38490644-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.6039A>G​(p.Lys2013=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,610,930 control chromosomes in the GnomAD database, including 7,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (549 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7175 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.832

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=-0.64).
• BP6: Variant 19-38490644-A-G is Benign according to our data. Variant chr19-38490644-A-G is described in ClinVar as [Benign]. Clinvar id is 93278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38490644-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.832 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6039A>G	p.Lys2013=	synonymous_variant	37/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6039A>G	p.Lys2013=	synonymous_variant	37/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6039A>G	p.Lys2013=	synonymous_variant	37/105	1		P4
RYR1	ENST00000599547.6	c.6039A>G	p.Lys2013=	synonymous_variant, NMD_transcript_variant	37/80	2

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11280 AN: 152152 Hom.: 552 Cov.: 32

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0727

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0968

Gnomad OTH AF: 0.0915

GnomAD3 exomes AF: 0.0907 AC: 22813 AN: 251388 Hom.: 1379 AF XY: 0.0961 AC XY: 13060 AN XY: 135868

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.0860

Gnomad ASJ exome AF: 0.0950

Gnomad EAS exome AF: 0.00266

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0957

Gnomad OTH exome AF: 0.0960

GnomAD4 exome AF: 0.0926 AC: 135001 AN: 1458660 Hom.: 7175 Cov.: 31 AF XY: 0.0959 AC XY: 69583 AN XY: 725926

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.0847

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.00647

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.0550

Gnomad4 NFE exome AF: 0.0924

Gnomad4 OTH exome AF: 0.0897

GnomAD4 genome AF: 0.0741 AC: 11283 AN: 152270 Hom.: 549 Cov.: 32 AF XY: 0.0736 AC XY: 5481 AN XY: 74456

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.0728

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.00462

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.0968

Gnomad4 OTH AF: 0.0924

Alfa AF: 0.0951 Hom.: 1292

Bravo AF: 0.0715

Asia WGS AF: 0.107 AC: 370 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.102

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	GeneDx	Feb 08, 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.Lys2013Lys in exon 37 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 9.8% (844/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2228068). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	-	- -

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. -

not provided Benign:1 Other:1

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

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	-0.64
CADD	Benign	2.6
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2228068; hg19: chr19-38981284; COSMIC: COSV62099401;