rs181590606

Positions:

chr19-38543894-T-C

Variant summary

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

The NM_000540.3(RYR1):c.12012+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,608,598 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 10 hom., cov: 32)

Exomes 𝑓: 0.018 ( 268 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.728

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=-0.79).

BP6

Variant 19-38543894-T-C is Benign according to our data. Variant chr19-38543894-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38543894-T-C is described in Lovd as [Benign]. Variant chr19-38543894-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1840/152290) while in subpopulation NFE AF= 0.0196 (1334/68012). AF 95% confidence interval is 0.0187. There are 10 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.12012+19T>C		intron_variant		ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.12012+19T>C		intron_variant		5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1840

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.0125

AC:

3074

AN:

245052

Hom.:

AF XY:

0.0128

AC XY:

1698

AN XY:

132776

show subpopulations

Gnomad AFR exome

AF:

0.00325

Gnomad AMR exome

AF:

0.00482

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.00499

Gnomad FIN exome

AF:

0.0145

Gnomad NFE exome

AF:

0.0195

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.0181

AC:

26384

AN:

1456308

Hom.:

268

Cov.:

AF XY:

0.0176

AC XY:

12773

AN XY:

724366

show subpopulations

Gnomad4 AFR exome

AF:

0.00246

Gnomad4 AMR exome

AF:

0.00506

Gnomad4 ASJ exome

AF:

0.0177

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00486

Gnomad4 FIN exome

AF:

0.0153

Gnomad4 NFE exome

AF:

0.0211

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0121

AC:

1840

AN:

152290

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

831

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00373

Gnomad4 AMR

AF:

0.00654

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.0134

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0113

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 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	PreventionGenetics, part of Exact Sciences	Mar 06, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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 22, 2023	- -

RYR1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.6

DANN

Benign

0.70

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