rs193922787

Positions:

• chr19-38490249-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000540.3(RYR1):​c.5988C>T​(p.Arg1996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -1.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.5988C>T	p.Arg1996=	synonymous_variant	36/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.5988C>T	p.Arg1996=	synonymous_variant	36/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.5988C>T	p.Arg1996=	synonymous_variant	36/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.5988C>T	p.Arg1996=	synonymous_variant, NMD_transcript_variant	36/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

RYR1 NM_000540.2 exon 36 p.Arg1996= (c.5988C>T): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar, but without additional information (Variation ID:133154). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, computational tools designed to predict splicing suggest that this variant may generate an alternate 5' splice site at this location. However, further studies are needed to understand its impact. Of note, this variant is a silent variant and does not change the amino acid. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -2
DS_DL_spliceai		0.95		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922787; hg19: chr19-38980889; COSMIC: COSV62097239;