rs2228072

Positions:

• chr19-38500876-G-A
• chr19-38500876-G-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.7500G>A​(p.Ala2500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,613,846 control chromosomes in the GnomAD database, including 9,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2500A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (913 hom., cov: 32)
  • Exomes 𝑓: 0.098 (8171 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -3.24

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=-0.73).
• BP6: Variant 19-38500876-G-A is Benign according to our data. Variant chr19-38500876-G-A is described in ClinVar as [Benign]. Clinvar id is 93287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38500876-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7500G>A	p.Ala2500=	synonymous_variant	47/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7500G>A	p.Ala2500=	synonymous_variant	47/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7500G>A	p.Ala2500=	synonymous_variant	47/105	1		P4
RYR1	ENST00000594335.5	c.954G>A	p.Ala318=	synonymous_variant, NMD_transcript_variant	8/49	1
RYR1	ENST00000599547.6	c.7500G>A	p.Ala2500=	synonymous_variant, NMD_transcript_variant	47/80	2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15563 AN: 151928 Hom.: 901 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0990

GnomAD3 exomes AF: 0.110 AC: 27615 AN: 251278 Hom.: 1867 AF XY: 0.114 AC XY: 15507 AN XY: 135868

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0912

Gnomad ASJ exome AF: 0.0745

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0984 AC: 143789 AN: 1461800 Hom.: 8171 Cov.: 51 AF XY: 0.102 AC XY: 73926 AN XY: 727200

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0922

Gnomad4 ASJ exome AF: 0.0769

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0894

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.103 AC: 15605 AN: 152046 Hom.: 913 Cov.: 32 AF XY: 0.104 AC XY: 7701 AN XY: 74330

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0757

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.0427

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0913 Hom.: 401

Bravo AF: 0.104

Asia WGS AF: 0.237 AC: 823 AN: 3478

EpiCase AF: 0.0955

EpiControl AF: 0.0947

ClinVar

Significance: Benign

Submissions summary: Benign:16

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 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala2500Ala in exon 47 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 12.0% (527/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2228072). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2014	- -
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, 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	-	- -

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

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

- -

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	-0.73
CADD	Benign	0.55
DANN	Benign	0.74

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: rs2228072; hg19: chr19-38991516; COSMIC: COSV62092593;