rs2945046

chr19-38548104-G-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.12095-129G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 982,350 control chromosomes in the GnomAD database, including 2,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (1442 hom., cov: 31)
  • Exomes 𝑓: 0.041 (1404 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.131

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=-0.89).
• BP6: Variant 19-38548104-G-C is Benign according to our data. Variant chr19-38548104-G-C is described in ClinVar as [Benign]. Clinvar id is 133031.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38548104-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12095-129G>C		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12095-129G>C		intron_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0954 AC: 14505 AN: 152070 Hom.: 1434 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0407 AC: 33757 AN: 830162 Hom.: 1404 AF XY: 0.0389 AC XY: 16698 AN XY: 429628

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.0945

Gnomad4 ASJ exome AF: 0.0384

Gnomad4 EAS exome AF: 0.0000897

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0328

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.0956 AC: 14554 AN: 152188 Hom.: 1442 Cov.: 31 AF XY: 0.0933 AC XY: 6938 AN XY: 74402

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.0687

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0341

Gnomad4 OTH AF: 0.0739

Alfa AF: 0.0704 Hom.: 100

Bravo AF: 0.106

Asia WGS AF: 0.0300 AC: 107 AN: 3478

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	-0.89
Cadd	Benign	1.2
Dann	Benign	0.63

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: rs2945046; hg19: chr19-39038744;