rs1468571

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.14256A>C(p.Thr4752Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.046 in 1,613,922 control chromosomes in the GnomAD database, including 5,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2016 hom., cov: 31)

Exomes 𝑓: 0.039 ( 3295 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.17

Variant links:

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]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 19-38578001-A-C is Benign according to our data. Variant chr19-38578001-A-C is described in ClinVar as [Benign]. Clinvar id is 93254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38578001-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.14256A>C	p.Thr4752Thr	synonymous_variant	Exon 98 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.14256A>C	p.Thr4752Thr	synonymous_variant	Exon 98 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17078

AN:

151952

Hom.:

1989

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.0733

Gnomad FIN

AF:

0.0490

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.0937

GnomAD3 exomes

AF:

0.0741

AC:

18620

AN:

251260

Hom.:

1566

AF XY:

0.0649

AC XY:

8818

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.300

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.0981

Gnomad SAS exome

AF:

0.0664

Gnomad FIN exome

AF:

0.0491

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0519

GnomAD4 exome

AF:

0.0391

AC:

57126

AN:

1461854

Hom.:

3295

Cov.:

AF XY:

0.0384

AC XY:

27924

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.301

Gnomad4 AMR exome

AF:

0.169

Gnomad4 ASJ exome

AF:

0.0162

Gnomad4 EAS exome

AF:

0.106

Gnomad4 SAS exome

AF:

0.0649

Gnomad4 FIN exome

AF:

0.0485

Gnomad4 NFE exome

AF:

0.0207

Gnomad4 OTH exome

AF:

0.0562

GnomAD4 genome

AF:

0.113

AC:

17162

AN:

152068

Hom.:

2016

Cov.:

AF XY:

0.114

AC XY:

8490

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.294

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.0176

Gnomad4 EAS

AF:

0.108

Gnomad4 SAS

AF:

0.0735

Gnomad4 FIN

AF:

0.0490

Gnomad4 NFE

AF:

0.0192

Gnomad4 OTH

AF:

0.0932

Alfa

AF:

0.0355

Hom.:

481

Bravo

AF:

0.129

Asia WGS

AF:

0.111

AC:

384

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0190

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Malignant hyperthermia, susceptibility to, 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 17, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1Other:1

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1-related disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.051

DANN

Benign

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over