rs2071090

chr19-38524814-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):c.10456-518T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,130 control chromosomes in the GnomAD database, including 1,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.15 (1871 hom., cov: 31)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.650

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10456-518T>C		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10456-518T>C		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10441-518T>C		intron_variant		1		P4
RYR1	ENST00000594335.5	c.*1184-518T>C		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.*1215-518T>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22588 AN: 152012 Hom.: 1861 Cov.: 31

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.149 AC: 22636 AN: 152130 Hom.: 1871 Cov.: 31 AF XY: 0.152 AC XY: 11276 AN XY: 74392

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.164

Alfa AF: 0.144 Hom.: 3513

Bravo AF: 0.152

Asia WGS AF: 0.319 AC: 1108 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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	-0.88
Cadd	Benign	18
Dann	Benign	0.71

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: rs2071090; hg19: chr19-39015454;