19-38519383-C-T

Position:

• chr19-38519383-C-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.10188C>T​(p.Asp3396=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,605,854 control chromosomes in the GnomAD database, including 1,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (199 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1530 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:1
• Conservation: PhyloP100: -1.58

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=-0.5).
• BP6: Variant 19-38519383-C-T is Benign according to our data. Variant chr19-38519383-C-T is described in ClinVar as [Benign]. Clinvar id is 93239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38519383-C-T is described in Lovd as [Benign]. Variant chr19-38519383-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10188C>T	p.Asp3396=	synonymous_variant	67/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10188C>T	p.Asp3396=	synonymous_variant	67/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10188C>T	p.Asp3396=	synonymous_variant	67/105	1		P4
RYR1	ENST00000594335.5	c.*931C>T		3_prime_UTR_variant, NMD_transcript_variant	27/49	1
RYR1	ENST00000599547.6	c.*947C>T		3_prime_UTR_variant, NMD_transcript_variant	66/80	2

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6330 AN: 152176 Hom.: 199 Cov.: 31

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0487

GnomAD3 exomes AF: 0.0444 AC: 10363 AN: 233166 Hom.: 335 AF XY: 0.0446 AC XY: 5620 AN XY: 126130

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.000176

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0498

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0421 AC: 61154 AN: 1453560 Hom.: 1530 Cov.: 32 AF XY: 0.0422 AC XY: 30469 AN XY: 722606

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.0772

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0416 AC: 6329 AN: 152294 Hom.: 199 Cov.: 31 AF XY: 0.0450 AC XY: 3348 AN XY: 74466

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0402

Gnomad4 ASJ AF: 0.0795

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0244

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0452 Hom.: 268

Bravo AF: 0.0355

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Asp3396Asp in exon 67 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 4.9% (424/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229145). -

not provided Uncertain:1 Benign:1 Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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: 17.256% in ExAC) 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. A synonymous variant not located in a splice region. -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

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 12, 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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.25
DANN	Benign	0.70

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: rs2229145; hg19: chr19-39010023; COSMIC: COSV62097516; COSMIC: COSV62097516;