rs2292799

Variant summary

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

The NM_000540.3(RYR1):c.11908-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,611,892 control chromosomes in the GnomAD database, including 828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 89 hom., cov: 32)

Exomes 𝑓: 0.023 ( 739 hom. )

Consequence

RYR1
NM_000540.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -0.144

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=-0.82).

BP6

Variant 19-38543757-A-G is Benign according to our data. Variant chr19-38543757-A-G is described in ClinVar as [Benign]. Clinvar id is 133022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38543757-A-G is described in Lovd as [Likely_benign]. Variant chr19-38543757-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.11908-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.11908-14A>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3458

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00789

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0720

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0610

Gnomad SAS

AF:

0.0333

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0347

AC:

8650

AN:

249418

Hom.:

279

AF XY:

0.0319

AC XY:

4313

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.00736

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0474

Gnomad SAS exome

AF:

0.0309

Gnomad FIN exome

AF:

0.0447

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0230

AC:

33543

AN:

1459946

Hom.:

739

Cov.:

AF XY:

0.0227

AC XY:

16506

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00636

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0681

Gnomad4 SAS exome

AF:

0.0293

Gnomad4 FIN exome

AF:

0.0441

Gnomad4 NFE exome

AF:

0.0173

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0228

AC:

3461

AN:

151946

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1893

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00784

Gnomad4 AMR

AF:

0.0723

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0609

Gnomad4 SAS

AF:

0.0334

Gnomad4 FIN

AF:

0.0444

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0240

Asia WGS

AF:

0.0590

AC:

205

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 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. -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2014	- -

Malignant hyperthermia, susceptibility to, 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2022	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Jan 12, 2018

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

-0.82

Cadd

Benign

0.97

Dann

Benign

0.54

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