rs143861818

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000540.3(RYR1):c.12283-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,794 control chromosomes in the GnomAD database, including 12 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 11 hom. )

Consequence

RYR1
NM_000540.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003926

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.528

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-38561106-C-T is Benign according to our data. Variant chr19-38561106-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=1, Benign=3}. Variant chr19-38561106-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00297 (4336/1461642) while in subpopulation NFE AF= 0.00352 (3918/1111822). AF 95% confidence interval is 0.00343. There are 11 homozygotes in gnomad4_exome. There are 2099 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.12283-7C>T		splice_region_variant, 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.12283-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00196

AC:

488

AN:

248440

Hom.:

AF XY:

0.00197

AC XY:

265

AN XY:

134774

show subpopulations

Gnomad AFR exome

AF:

0.000558

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00312

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00297

AC:

4336

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

2099

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.000655

Gnomad4 NFE exome

AF:

0.00352

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152152

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00337

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00204

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 01, 2016	- -

Malignant hyperthermia, susceptibility to, 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2018	- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

Invitae

Jan 31, 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

-0.84

Cadd

Benign

1.5

Dann

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

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