19-38565651-C-T

Position:

chr19-38565651-C-T

Variant summary

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

The NM_000540.3(RYR1):c.13317C>T(p.Ala4439=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,388,862 control chromosomes in the GnomAD database, including 1,462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 201 hom., cov: 31)

Exomes 𝑓: 0.043 ( 1261 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13O:1

Conservation

PhyloP100: -2.00

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=-0.58).

BP6

Variant 19-38565651-C-T is Benign according to our data. Variant chr19-38565651-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565651-C-T is described in Lovd as [Benign]. Variant chr19-38565651-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0595 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.13317C>T	p.Ala4439=	synonymous_variant	91/106	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.13317C>T	p.Ala4439=	synonymous_variant	91/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6334

AN:

151964

Hom.:

201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0804

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.0505

Gnomad OTH

AF:

0.0499

GnomAD3 exomes

AF:

0.0545

AC:

769

AN:

14112

Hom.:

AF XY:

0.0554

AC XY:

455

AN XY:

8206

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.0439

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0520

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.0566

Gnomad OTH exome

AF:

0.0488

GnomAD4 exome

AF:

0.0426

AC:

52680

AN:

1236784

Hom.:

1261

Cov.:

AF XY:

0.0428

AC XY:

25815

AN XY:

602802

show subpopulations

Gnomad4 AFR exome

AF:

0.0105

Gnomad4 AMR exome

AF:

0.0373

Gnomad4 ASJ exome

AF:

0.0801

Gnomad4 EAS exome

AF:

0.000213

Gnomad4 SAS exome

AF:

0.0364

Gnomad4 FIN exome

AF:

0.110

Gnomad4 NFE exome

AF:

0.0422

Gnomad4 OTH exome

AF:

0.0446

GnomAD4 genome

AF:

0.0416

AC:

6331

AN:

152078

Hom.:

201

Cov.:

AF XY:

0.0449

AC XY:

3336

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0113

Gnomad4 AMR

AF:

0.0399

Gnomad4 ASJ

AF:

0.0804

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.0347

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.0504

Gnomad4 OTH

AF:

0.0489

Alfa

AF:

0.0277

Hom.:

Bravo

AF:

0.0352

Asia WGS

AF:

0.0170

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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	p.Ala4439Ala in exon 91 of RYR1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 9.7% (18/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http:// www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs113579185). -
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)	May 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 29, 2018	- -

not provided

Uncertain:1Benign:2Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 16.154% in ExAC) based on the frequency threshold of 2.223% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.29

DANN

Benign

0.96

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