rs2288888

Positions:

• chr19-38455542-G-A
• chr19-38455542-G-C

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.1668G>A​(p.Ser556Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,613,334 control chromosomes in the GnomAD database, including 347,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31370 hom., cov: 31)
  • Exomes 𝑓: 0.65 (316245 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: -4.99

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=-0.68).
• BP6: Variant 19-38455542-G-A is Benign according to our data. Variant chr19-38455542-G-A is described in ClinVar as [Benign]. Clinvar id is 93258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38455542-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1668G>A	p.Ser556Ser	synonymous_variant	15/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1668G>A	p.Ser556Ser	synonymous_variant	15/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1668G>A	p.Ser556Ser	synonymous_variant	15/105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1668G>A		non_coding_transcript_exon_variant	15/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96765 AN: 151790 Hom.: 31361 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.656

GnomAD3 exomes AF: 0.642 AC: 161310 AN: 251256 Hom.: 52669 AF XY: 0.636 AC XY: 86369 AN XY: 135802

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.618

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.705

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.655 AC: 957134 AN: 1461426 Hom.: 316245 Cov.: 48 AF XY: 0.650 AC XY: 472495 AN XY: 727002

Gnomad4 AFR exome AF: 0.548

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.637 AC: 96812 AN: 151908 Hom.: 31370 Cov.: 31 AF XY: 0.635 AC XY: 47112 AN XY: 74250

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.449

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.650

Alfa AF: 0.664 Hom.: 52319

Bravo AF: 0.638

Asia WGS AF: 0.459 AC: 1599 AN: 3478

EpiCase AF: 0.678

EpiControl AF: 0.687

ClinVar

Significance: Benign

Submissions summary: Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ser556Ser in exon 15 of RYR1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 44.6% (1965/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2288888). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 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. -
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	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RYR1: BP4, BP7, BS1, BS2 -

Congenital multicore myopathy with external ophthalmoplegia 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	Genome-Nilou Lab	Nov 07, 2021	- -

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 29, 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 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

- -

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

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.85

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: rs2288888; hg19: chr19-38946182; COSMIC: COSV62095035;