rs1469695

Positions:

• chr19-38502732-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.7835+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,416,812 control chromosomes in the GnomAD database, including 70,145 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (8710 hom., cov: 20)
  • Exomes 𝑓: 0.32 (61435 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004438
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 0.157

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-38502732-A-G is Benign according to our data. Variant chr19-38502732-A-G is described in ClinVar as [Benign]. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7835+5A>G		splice_region_variant, intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7835+5A>G		splice_region_variant, intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7835+5A>G		splice_region_variant, intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1286+5A>G		splice_region_variant, intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7835+5A>G		splice_region_variant, intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 47409 AN: 122054 Hom.: 8680 Cov.: 20

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.396

GnomAD3 exomes AF: 0.335 AC: 76265 AN: 227728 Hom.: 13438 AF XY: 0.333 AC XY: 41589 AN XY: 125058

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.344

Gnomad SAS exome AF: 0.451

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.316 AC: 408965 AN: 1294658 Hom.: 61435 Cov.: 38 AF XY: 0.320 AC XY: 206197 AN XY: 643496

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.463

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.398

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.389 AC: 47491 AN: 122154 Hom.: 8710 Cov.: 20 AF XY: 0.403 AC XY: 23373 AN XY: 57968

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.401

Alfa AF: 0.296 Hom.: 2057

Bravo AF: 0.351

Asia WGS AF: 0.458 AC: 1533 AN: 3356

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.7835+5A>G in intron 48 of RYR1: This variant is not expected to have clinical significance because it has been identified in 44.2% (1949/4406) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs1469695). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Uncertain:1 Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
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: 46.669% 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. 9 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

Malignant hyperthermia, susceptibility to, 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.1
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs1469695; hg19: chr19-38993372; COSMIC: COSV62089426;