19-38499696-C-T

Position:

• chr19-38499696-C-T

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.7089C>T​(p.Cys2363=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,600,574 control chromosomes in the GnomAD database, including 2,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (363 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2560 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12 O:1
• Conservation: PhyloP100: 0.339

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=-0.38).
• BP6: Variant 19-38499696-C-T is Benign according to our data. Variant chr19-38499696-C-T is described in ClinVar as [Benign]. Clinvar id is 93284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38499696-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.339 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7089C>T	p.Cys2363=	synonymous_variant	44/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7089C>T	p.Cys2363=	synonymous_variant	44/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7089C>T	p.Cys2363=	synonymous_variant	44/105	1		P4
RYR1	ENST00000594335.5	c.543C>T	p.Cys181=	synonymous_variant, NMD_transcript_variant	5/49	1
RYR1	ENST00000599547.6	c.7089C>T	p.Cys2363=	synonymous_variant, NMD_transcript_variant	44/80	2

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10095 AN: 152058 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0657

Gnomad ASJ AF: 0.0951

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0748

GnomAD3 exomes AF: 0.0677 AC: 16176 AN: 238894 Hom.: 615 AF XY: 0.0677 AC XY: 8837 AN XY: 130576

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.0468

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.0556

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0570

Gnomad OTH exome AF: 0.0813

GnomAD4 exome AF: 0.0553 AC: 80027 AN: 1448398 Hom.: 2560 Cov.: 34 AF XY: 0.0559 AC XY: 40277 AN XY: 720974

Gnomad4 AFR exome AF: 0.0592

Gnomad4 AMR exome AF: 0.0496

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0549

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.0489

Gnomad4 OTH exome AF: 0.0635

GnomAD4 genome AF: 0.0664 AC: 10098 AN: 152176 Hom.: 363 Cov.: 32 AF XY: 0.0702 AC XY: 5220 AN XY: 74388

Gnomad4 AFR AF: 0.0578

Gnomad4 AMR AF: 0.0655

Gnomad4 ASJ AF: 0.0951

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0551

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.0575

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.0601 Hom.: 110

Bravo AF: 0.0631

Asia WGS AF: 0.0990 AC: 344 AN: 3476

EpiCase AF: 0.0617

EpiControl AF: 0.0590

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2013	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Cys2363Cys in exon 44 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 5.7% (490/8598) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2228071). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2015	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. -

not provided Uncertain:1 Benign:1 Other:1

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: 13.989% 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 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. -

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. -

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	-0.38
CADD	Benign	9.3
DANN	Benign	0.76

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: rs2228071; hg19: chr19-38990336; COSMIC: COSV62097478;