19-38506819-G-C

Position:

• chr19-38506819-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.8693-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,554 control chromosomes in the GnomAD database, including 67,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8640 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58930 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Scores: Splicing: ADA: 0.009549
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: -0.424

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-38506819-G-C is Benign according to our data. Variant chr19-38506819-G-C is described in ClinVar as [Benign]. Clinvar id is 93302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38506819-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8693-10G>C		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8693-10G>C		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8693-10G>C		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.2144-10G>C		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8693-10G>C		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49482 AN: 151850 Hom.: 8604 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.321 AC: 80464 AN: 250388 Hom.: 13878 AF XY: 0.321 AC XY: 43514 AN XY: 135458

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403140 AN: 1461584 Hom.: 58930 Cov.: 44 AF XY: 0.280 AC XY: 203825 AN XY: 727098

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.326 AC: 49579 AN: 151970 Hom.: 8640 Cov.: 31 AF XY: 0.333 AC XY: 24772 AN XY: 74282

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.337

Alfa AF: 0.268 Hom.: 1116

Bravo AF: 0.333

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.8693-10G>C in intron 56 of RYR1: This variant is not expected to have clinical significance because it has been identified in 42.6% (1877/4406) of African Ame rican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2915958). -
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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Uncertain:1 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	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 45.816% in gnomAD_Exomes) based on the frequency threshold of 2.223% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 9 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

Congenital multicore myopathy with external ophthalmoplegia 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	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. -

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 28, 2019	- -

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	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 04, 2025

- -

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

- -

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

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.4
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0095
dbscSNV1_RF	Benign	0.052
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: rs2915958; hg19: chr19-38997459; COSMIC: COSV62092647; COSMIC: COSV62092647;