rs2915953

Positions:

• chr19-38505426-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BA1 BP7

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.8400+28A>G in RYR1 is an intronic variant located in intron 53. The filtering allele frequency (the lower threshold of the 95% CI of 37922/85572, 8751 homozygotes) of the c.8400+28A>G variant in RYR1 is 0.4383 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.8400+28A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024918/MONDO:0100150/179

• Frequency:
  • Genomes: 𝑓 0.33 (8637 hom., cov: 31)
  • Exomes 𝑓: 0.27 (53110 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: 0.874

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 -10 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.
• BA1: 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.8400+28A>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.8400+28A>G		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8400+28A>G		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1851+28A>G		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8400+28A>G		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49483 AN: 151922 Hom.: 8602 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.314 AC: 63093 AN: 200948 Hom.: 10486 AF XY: 0.314 AC XY: 34029 AN XY: 108430

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.327

Gnomad SAS exome AF: 0.452

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.271 AC: 367589 AN: 1356708 Hom.: 53110 Cov.: 22 AF XY: 0.276 AC XY: 186516 AN XY: 676690

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.326 AC: 49579 AN: 152040 Hom.: 8637 Cov.: 31 AF XY: 0.333 AC XY: 24760 AN XY: 74306

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.338

Alfa AF: 0.268 Hom.: 1668

Bravo AF: 0.333

Asia WGS AF: 0.487 AC: 1691 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2013

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RYR1-related myopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The variant NM_000540.3:c.8400+28A>G in RYR1 is an intronic variant located in intron 53. The filtering allele frequency (the lower threshold of the 95% CI of 37922/85572, 8751 homozygotes) of the c.8400+28A>G variant in RYR1 is 0.4383 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.8400+28A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Central core myopathy 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	-0.91
CADD	Benign	9.1
DANN	Benign	0.77

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: rs2915953; hg19: chr19-38996066; COSMIC: COSV62092754;