rs537751969

Positions:

• chr19-38448637-CT-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: The c.985-11del (NM_000540.3(RYR1):c.958-11del) variant in RYR1 is an intronic variant, located in intron 10 and 11 bases upstream of exon 11. The filtering allele frequency (the lower threshold of the 95% CI of 1684/64032 with 32 homozygous observations) of the c.958-11del variant in RYR1 is 0.0001110 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain, suggesting that the variant has no impact on splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4/BP7). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathies, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA073846/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.0020 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: RYR1 NM_000540.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign reviewed by expert panel B:9
• Conservation: PhyloP100: 1.45

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 Likely_benign. Variant got -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.958-11del		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.958-11del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.958-11del		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.958-11del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152248 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00269 AC: 677 AN: 251324 Hom.: 5 AF XY: 0.00255 AC XY: 347 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00112 AC: 1632 AN: 1461870 Hom.: 24 Cov.: 31 AF XY: 0.00105 AC XY: 764 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152366 Hom.: 7 Cov.: 31 AF XY: 0.00319 AC XY: 238 AN XY: 74506

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0257

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 06, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Malignant hyperthermia of anesthesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related myopathy Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.985-11del (NM_000540.3(RYR1):c.958-11del) variant in RYR1 is an intronic variant, located in intron 10 and 11 bases upstream of exon 11. The filtering allele frequency (the lower threshold of the 95% CI of 1684/64032 with 32 homozygous observations) of the c.958-11del variant in RYR1 is 0.0001110 for European (non-Finnish) chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0000006) for BS1, and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor gain, suggesting that the variant has no impact on splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC genome browser (BP4/BP7). In summary, this variant meets the criteria to be classified as likely benign for RYR1-related myopathies, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1, BP4, BP7 (Congenital Myopathies VCEP Specifications Version 1; 8/7/2024). -

Multiminicore myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs537751969; hg19: chr19-38939277;