rs146072491

chr19-38580447-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000540.3(RYR1):c.14589C>T(p.Phe4863=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,614,160 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0063 (52 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.42

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=-0.22).
• BP6: Variant 19-38580447-C-T is Benign according to our data. Variant chr19-38580447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38580447-C-T is described in Lovd as [Likely_benign]. Variant chr19-38580447-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0059 (899/152282) while in subpopulation NFE AF= 0.00576 (392/68034). AF 95% confidence interval is 0.00529. There are 11 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14589C>T	p.Phe4863=	synonymous_variant	101/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14589C>T	p.Phe4863=	synonymous_variant	101/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 899 AN: 152162 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0394

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00609 AC: 1531 AN: 251478 Hom.: 10 AF XY: 0.00611 AC XY: 831 AN XY: 135912

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00628 AC: 9181 AN: 1461878 Hom.: 52 Cov.: 34 AF XY: 0.00606 AC XY: 4410 AN XY: 727240

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.00626

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152282 Hom.: 11 Cov.: 31 AF XY: 0.00721 AC XY: 537 AN XY: 74434

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0394

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00493 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 22, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 29, 2022	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RYR1: BP4, BS2 -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 22, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-Related Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	12
Dann	Benign	0.75

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: rs146072491; hg19: chr19-39071087;