19-38501000-C-G

Position:

• chr19-38501000-C-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.7614+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,610,936 control chromosomes in the GnomAD database, including 29,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4562 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25122 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 0.348

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=-0.73).
• BP6: Variant 19-38501000-C-G is Benign according to our data. Variant chr19-38501000-C-G is described in ClinVar as [Benign]. Clinvar id is 93289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38501000-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7614+10C>G		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7614+10C>G		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7614+10C>G		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1065+10C>G		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7614+10C>G		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35106 AN: 152002 Hom.: 4546 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.214 AC: 51936 AN: 242586 Hom.: 5988 AF XY: 0.209 AC XY: 27460 AN XY: 131646

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.179 AC: 261471 AN: 1458818 Hom.: 25122 Cov.: 39 AF XY: 0.180 AC XY: 130547 AN XY: 725520

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.231 AC: 35156 AN: 152118 Hom.: 4562 Cov.: 32 AF XY: 0.235 AC XY: 17501 AN XY: 74354

Gnomad4 AFR AF: 0.341

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.234

Alfa AF: 0.125 Hom.: 281

Bravo AF: 0.239

Asia WGS AF: 0.249 AC: 867 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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.7614+10C>G in intron 47 of RYR1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 33.2% (1463/4406) of African American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2960323). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2014	- -
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 22, 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. -

not provided Uncertain:1 Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
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: 36.177% 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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

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	Genome-Nilou Lab	Nov 07, 2021	- -

Central core myopathy Benign:2

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	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

- -

Malignant hyperthermia, susceptibility to, 1 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. -

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	-0.73
CADD	Benign	6.6
DANN	Benign	0.67

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

Other links and lift over

dbSNP: rs2960323; hg19: chr19-38991640; COSMIC: COSV62101652;