rs16972636

chr19-38473469-T-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.3858T>C(p.Leu1286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 1,613,736 control chromosomes in the GnomAD database, including 937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (455 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (482 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.227

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=-0.61).
• BP6: Variant 19-38473469-T-C is Benign according to our data. Variant chr19-38473469-T-C is described in ClinVar as [Benign]. Clinvar id is 93264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38473469-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.227 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.3858T>C	p.Leu1286=	synonymous_variant	28/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.3858T>C	p.Leu1286=	synonymous_variant	28/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.3858T>C	p.Leu1286=	synonymous_variant	28/105	1		P4
RYR1	ENST00000599547.6	c.3858T>C	p.Leu1286=	synonymous_variant, NMD_transcript_variant	28/80	2

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6558 AN: 151966 Hom.: 449 Cov.: 31

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.0350

GnomAD3 exomes AF: 0.0118 AC: 2946 AN: 249626 Hom.: 202 AF XY: 0.00848 AC XY: 1146 AN XY: 135212

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.00979

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000685

Gnomad OTH exome AF: 0.00786

GnomAD4 exome AF: 0.00488 AC: 7129 AN: 1461652 Hom.: 482 Cov.: 33 AF XY: 0.00421 AC XY: 3060 AN XY: 727156

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0433 AC: 6586 AN: 152084 Hom.: 455 Cov.: 31 AF XY: 0.0423 AC XY: 3143 AN XY: 74370

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000589

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.0140 Hom.: 35

Bravo AF: 0.0504

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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	Eurofins Ntd Llc (ga)	May 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Jun 14, 2016

- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 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	-0.61
Cadd	Benign	4.4
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: rs16972636; hg19: chr19-38964109;