19-38500960-C-T

Variant names:

• chr19-38500960-C-T
• rs1465698
• NM_000540.3:c.7584C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.7584C>T​(p.Pro2528Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,613,114 control chromosomes in the GnomAD database, including 248 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 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (211 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -4.93

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-38500960-C-T is Benign according to our data. Variant chr19-38500960-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38500960-C-T is described in Lovd as [Likely_benign]. Variant chr19-38500960-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7584C>T	p.Pro2528Pro	synonymous_variant	Exon 47 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7584C>T	p.Pro2528Pro	synonymous_variant	Exon 47 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7584C>T	p.Pro2528Pro	synonymous_variant	Exon 47 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1035C>T		non_coding_transcript_exon_variant	Exon 8 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7584C>T		non_coding_transcript_exon_variant	Exon 47 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1854 AN: 152126 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0155 AC: 3811 AN: 245820 Hom.: 99 AF XY: 0.0139 AC XY: 1857 AN XY: 133458

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0602

Gnomad SAS exome AF: 0.0212

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.000764

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00572 AC: 8354 AN: 1460870 Hom.: 211 Cov.: 41 AF XY: 0.00602 AC XY: 4378 AN XY: 726706

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.0418

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.000378

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.00890

GnomAD4 genome AF: 0.0122 AC: 1854 AN: 152244 Hom.: 37 Cov.: 32 AF XY: 0.0137 AC XY: 1023 AN XY: 74448

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.0679

Gnomad4 SAS AF: 0.0266

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00416 Hom.: 9

Bravo AF: 0.0152

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 11, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 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. -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

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. -

Sep 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 03, 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: Likely 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	-0.58
CADD	Benign	1.5
DANN	Benign	0.66

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: rs1465698; hg19: chr19-38991600; COSMIC: COSV62088375;