rs2960347

Positions:

• chr19-38507039-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.8816+87G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,592,224 control chromosomes in the GnomAD database, including 65,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8305 hom., cov: 30)
  • Exomes 𝑓: 0.27 (56834 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.73

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-38507039-G-T is Benign according to our data. Variant chr19-38507039-G-T is described in ClinVar as [Benign]. Clinvar id is 133236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38507039-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8816+87G>T		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8816+87G>T		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8816+87G>T		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.2267+87G>T		intron_variant		1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8816+87G>T		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.323 AC: 48705 AN: 150820 Hom.: 8270 Cov.: 30

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.329

GnomAD4 exome AF: 0.273 AC: 393083 AN: 1441286 Hom.: 56834 AF XY: 0.277 AC XY: 198822 AN XY: 716994

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.323 AC: 48801 AN: 150938 Hom.: 8305 Cov.: 30 AF XY: 0.330 AC XY: 24327 AN XY: 73666

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.458

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.334

Alfa AF: 0.280 Hom.: 784

Bravo AF: 0.332

Asia WGS AF: 0.486 AC: 1686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 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)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.63
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2960347; hg19: chr19-38997679; COSMIC: COSV62093046; COSMIC: COSV62093046;