rs77592501

Positions:

chr19-38527637-C-T

Variant summary

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

The NM_000540.3(RYR1):c.10687-10C>T 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 0.0613 in 1,613,786 control chromosomes in the GnomAD database, including 4,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 382 hom., cov: 32)

Exomes 𝑓: 0.062 ( 4431 hom. )

Consequence

RYR1
NM_000540.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00006909

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.227

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:

(HGNC:):

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=-0.81).

BP6

Variant 19-38527637-C-T is Benign according to our data. Variant chr19-38527637-C-T is described in ClinVar as [Benign]. Clinvar id is 93241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38527637-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 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.10687-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.10687-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	ENSP00000352608	A2	P21817-1
	ENST00000597015.1 linkuse as main transcript	n.374G>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

AF:

0.0528

AC:

8038

AN:

152182

Hom.:

382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.0599

Gnomad ASJ

AF:

0.0608

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0502

Gnomad OTH

AF:

0.0569

GnomAD3 exomes

AF:

0.0791

AC:

19766

AN:

250028

Hom.:

1324

AF XY:

0.0854

AC XY:

11558

AN XY:

135328

show subpopulations

Gnomad AFR exome

AF:

0.0237

Gnomad AMR exome

AF:

0.0632

Gnomad ASJ exome

AF:

0.0668

Gnomad EAS exome

AF:

0.162

Gnomad SAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0735

GnomAD4 exome

AF:

0.0622

AC:

90853

AN:

1461486

Hom.:

4431

Cov.:

AF XY:

0.0667

AC XY:

48494

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.0252

Gnomad4 AMR exome

AF:

0.0629

Gnomad4 ASJ exome

AF:

0.0650

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.213

Gnomad4 FIN exome

AF:

0.0317

Gnomad4 NFE exome

AF:

0.0493

Gnomad4 OTH exome

AF:

0.0673

GnomAD4 genome

AF:

0.0528

AC:

8040

AN:

152300

Hom.:

382

Cov.:

AF XY:

0.0553

AC XY:

4120

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.0596

Gnomad4 ASJ

AF:

0.0608

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.227

Gnomad4 FIN

AF:

0.0267

Gnomad4 NFE

AF:

0.0502

Gnomad4 OTH

AF:

0.0629

Alfa

AF:

0.0457

Hom.:

Bravo

AF:

0.0498

Asia WGS

AF:

0.227

AC:

787

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2014	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.10687-10C>T in intron 72 of RYR1: This variant is not expected to have clinica l significance because it has been identified in 4.8% (416/8600) of European Ame rican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs77592501). -
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	Aug 17, 2022	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

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

- -

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

-0.81

CADD

Benign

8.6

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000069

dbscSNV1_RF

Benign

0.0060

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