rs143752962

Positions:

chr19-38519461-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000540.3(RYR1):c.10259+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,587,772 control chromosomes in the GnomAD database, including 144 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 135 hom. )

Consequence

RYR1
NM_000540.3 splice_region, intron

Scores

Splicing: ADA: 0.00002227

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.565

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=-0.89).

BP6

Variant 19-38519461-G-A is Benign according to our data. Variant chr19-38519461-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38519461-G-A is described in Lovd as [Likely_benign]. Variant chr19-38519461-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00859 (1307/152196) while in subpopulation NFE AF= 0.0137 (932/68008). AF 95% confidence interval is 0.013. There are 9 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.10259+7G>A		splice_region_variant, intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.10259+7G>A	splice_region_variant, intron_variant	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.10259+7G>A	splice_region_variant, intron_variant	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.*1002+7G>A	splice_region_variant, intron_variant, NMD_transcript_variant	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.*1018+7G>A	splice_region_variant, intron_variant, NMD_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00859

AC:

1307

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.00866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00717

AC:

1465

AN:

204272

Hom.:

AF XY:

0.00739

AC XY:

813

AN XY:

110036

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.00657

Gnomad ASJ exome

AF:

0.00852

Gnomad EAS exome

AF:

0.0000674

Gnomad SAS exome

AF:

0.00247

Gnomad FIN exome

AF:

0.00168

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00838

GnomAD4 exome

AF:

0.0117

AC:

16777

AN:

1435576

Hom.:

135

Cov.:

AF XY:

0.0114

AC XY:

8094

AN XY:

712208

show subpopulations

Gnomad4 AFR exome

AF:

0.00172

Gnomad4 AMR exome

AF:

0.00691

Gnomad4 ASJ exome

AF:

0.00962

Gnomad4 EAS exome

AF:

0.0000266

Gnomad4 SAS exome

AF:

0.00296

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00859

AC:

1307

AN:

152196

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

587

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00253

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.00866

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00875

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RYR1: BP4, BS1, BS2 -

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

- -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

-0.89

CADD

Benign

0.50

DANN

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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