chr19-38502907-C-T

Position:

• chr19-38502907-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.7863C>T​(p.His2621=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,610,390 control chromosomes in the GnomAD database, including 21,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2367 hom., cov: 30)
  • Exomes 𝑓: 0.15 (18634 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:17 O:1
• Conservation: PhyloP100: -0.284

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=-0.4).
• BP6: Variant 19-38502907-C-T is Benign according to our data. Variant chr19-38502907-C-T is described in ClinVar as [Benign]. Clinvar id is 93294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502907-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7863C>T	p.His2621=	synonymous_variant	49/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7863C>T	p.His2621=	synonymous_variant	49/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7863C>T	p.His2621=	synonymous_variant	49/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1317C>T	p.His439=	synonymous_variant, NMD_transcript_variant	10/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.7863C>T	p.His2621=	synonymous_variant, NMD_transcript_variant	49/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25762 AN: 151396 Hom.: 2356 Cov.: 30

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.176

GnomAD3 exomes AF: 0.178 AC: 44347 AN: 249480 Hom.: 4516 AF XY: 0.181 AC XY: 24493 AN XY: 135000

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.285

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.153 AC: 222891 AN: 1458878 Hom.: 18634 Cov.: 37 AF XY: 0.157 AC XY: 113791 AN XY: 725842

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.170 AC: 25809 AN: 151512 Hom.: 2367 Cov.: 30 AF XY: 0.175 AC XY: 12985 AN XY: 74034

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.303

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.182

Alfa AF: 0.108 Hom.: 257

Bravo AF: 0.171

Asia WGS AF: 0.337 AC: 1167 AN: 3472

EpiCase AF: 0.156

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -
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	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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	PreventionGenetics, part of Exact Sciences	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His2621His in exon 49 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 18.9% (834/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229142). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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: 29.482% 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. A synonymous variant not located in a splice region. -
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: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. -

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. -

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

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

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.3
DANN	Benign	0.93

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: rs2229142; hg19: chr19-38993547; COSMIC: COSV62092485;