rs45585535

Positions:

• chr19-38466086-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.2871-5C>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 0.0314 in 1,605,616 control chromosomes in the GnomAD database, including 1,122 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 0.030 (136 hom., cov: 32)
  • Exomes 𝑓: 0.032 (986 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001598
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.857

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=-0.81).
• BP6: Variant 19-38466086-C-T is Benign according to our data. Variant chr19-38466086-C-T is described in ClinVar as [Benign]. Clinvar id is 93260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38466086-C-T is described in Lovd as [Likely_benign]. Variant chr19-38466086-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.03 (4566/152264) while in subpopulation NFE AF= 0.0377 (2563/68012). AF 95% confidence interval is 0.0365. There are 136 homozygotes in gnomad4. There are 2473 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 136 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.2871-5C>T		splice_region_variant, splice_polypyrimidine_tract_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.2871-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.2871-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.2871-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000471601
RYR1	ENST00000594111.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4569 AN: 152146 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0267

GnomAD3 exomes AF: 0.0307 AC: 7110 AN: 231340 Hom.: 218 AF XY: 0.0301 AC XY: 3792 AN XY: 126006

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00890

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0338

GnomAD4 exome AF: 0.0316 AC: 45921 AN: 1453352 Hom.: 986 Cov.: 30 AF XY: 0.0312 AC XY: 22509 AN XY: 722488

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.0000766

Gnomad4 SAS exome AF: 0.00875

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0325

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0300 AC: 4566 AN: 152264 Hom.: 136 Cov.: 32 AF XY: 0.0332 AC XY: 2473 AN XY: 74442

Gnomad4 AFR AF: 0.00513

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0312 Hom.: 65

Bravo AF: 0.0224

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 26, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.2871-5C>T in intron 23 of RYR1: This variant is not expected to have clinical significance because it has been identified in 3.3% (284/8590) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs45585535). -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.87
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
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: rs45585535; hg19: chr19-38956726;