rs55845760

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000540.3(RYR1):c.4161-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,573,956 control chromosomes in the GnomAD database, including 16,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 4094 hom., cov: 31)

Exomes 𝑓: 0.12 ( 12594 hom. )

Consequence

RYR1
NM_000540.3 splice_region, intron

Scores

Splicing: ADA: 0.00001653

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0800

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 19-38475312-T-C is Benign according to our data. Variant chr19-38475312-T-C is described in ClinVar as [Benign]. Clinvar id is 93268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38475312-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.4161-6T>C		splice_region_variant, intron_variant		ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.4161-6T>C	splice_region_variant, intron_variant	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.4161-6T>C	splice_region_variant, intron_variant	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.4161-6T>C	splice_region_variant, intron_variant	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28558

AN:

151868

Hom.:

4069

Cov.:

show subpopulations

Gnomad AFR

AF:

0.398

Gnomad AMI

AF:

0.0584

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.0553

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.172

GnomAD3 exomes

AF:

0.132

AC:

25049

AN:

189394

Hom.:

2338

AF XY:

0.132

AC XY:

13376

AN XY:

101206

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.0344

Gnomad SAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.120

AC:

171216

AN:

1421970

Hom.:

12594

Cov.:

AF XY:

0.123

AC XY:

86393

AN XY:

703754

show subpopulations

Gnomad4 AFR exome

AF:

0.412

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.128

Gnomad4 EAS exome

AF:

0.0397

Gnomad4 SAS exome

AF:

0.202

Gnomad4 FIN exome

AF:

0.0624

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.188

AC:

28635

AN:

151986

Hom.:

4094

Cov.:

AF XY:

0.185

AC XY:

13775

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.399

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.133

Gnomad4 EAS

AF:

0.0435

Gnomad4 SAS

AF:

0.209

Gnomad4 FIN

AF:

0.0553

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.174

Alfa

AF:

0.155

Hom.:

1333

Bravo

AF:

0.200

Asia WGS

AF:

0.163

AC:

566

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Malignant hyperthermia, susceptibility to, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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. -

RYR1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Central core myopathy

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

-0.93

CADD

Benign

2.0

DANN

Benign

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.014

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