19-38469040-C-T

Variant names:

• chr19-38469040-C-T
• rs11083462
• NM_000540.3:c.3456C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.3456C>T​(p.Ile1152Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,670 control chromosomes in the GnomAD database, including 114,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11569 hom., cov: 31)
  • Exomes 𝑓: 0.37 (103147 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -3.62

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 19-38469040-C-T is Benign according to our data. Variant chr19-38469040-C-T is described in ClinVar as [Benign]. Clinvar id is 93263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38469040-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.3456C>T	p.Ile1152Ile	synonymous_variant	Exon 26 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.3456C>T	p.Ile1152Ile	synonymous_variant	Exon 26 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.3456C>T	p.Ile1152Ile	synonymous_variant	Exon 26 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.3456C>T		non_coding_transcript_exon_variant	Exon 26 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58610 AN: 151858 Hom.: 11545 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.371

GnomAD3 exomes AF: 0.391 AC: 98237 AN: 251440 Hom.: 20019 AF XY: 0.395 AC XY: 53695 AN XY: 135898

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.372 AC: 543190 AN: 1461694 Hom.: 103147 Cov.: 48 AF XY: 0.376 AC XY: 273642 AN XY: 727162

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.386 AC: 58678 AN: 151976 Hom.: 11569 Cov.: 31 AF XY: 0.392 AC XY: 29091 AN XY: 74256

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.376

Alfa AF: 0.358 Hom.: 19960

Bravo AF: 0.378

Asia WGS AF: 0.548 AC: 1903 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.345

ClinVar

Significance: Benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Apr 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile1152Ile in exon 26 of RYR1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 43.8% (1932/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11083462). -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

RYR1-related disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	5.6
DANN	Benign	0.82

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: rs11083462; hg19: chr19-38959680; COSMIC: COSV62092707; COSMIC: COSV62092707;