rs2254484

Positions:

• chr19-38526738-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000540.3(RYR1):​c.10627-255T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 151,842 control chromosomes in the GnomAD database, including 6,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6636 hom., cov: 30)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.607

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-38526738-T-C is Benign according to our data. Variant chr19-38526738-T-C is described in ClinVar as [Benign]. Clinvar id is 132998.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38526738-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.10627-255T>C		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.10627-255T>C		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.10612-255T>C		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.*1355-255T>C		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.*1386-255T>C		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42481 AN: 151724 Hom.: 6601 Cov.: 30

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.280 AC: 42574 AN: 151842 Hom.: 6636 Cov.: 30 AF XY: 0.287 AC XY: 21322 AN XY: 74180

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.282

Alfa AF: 0.236 Hom.: 581

Bravo AF: 0.291

Asia WGS AF: 0.416 AC: 1445 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

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 provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.88
DANN	Benign	0.33

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: rs2254484; hg19: chr19-39017378;