rs2960336

Positions:

• chr19-38511500-C-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.9123-61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,572,146 control chromosomes in the GnomAD database, including 4,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1203 hom., cov: 31)
  • Exomes 𝑓: 0.056 (3234 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.881

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=-0.86).
• BP6: Variant 19-38511500-C-T is Benign according to our data. Variant chr19-38511500-C-T is described in ClinVar as [Benign]. Clinvar id is 133237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38511500-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.9123-61C>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.9123-61C>T		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.9123-61C>T		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.2575-572C>T		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.9123-61C>T		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15163 AN: 151810 Hom.: 1196 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0510

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0934

GnomAD4 exome AF: 0.0560 AC: 79539 AN: 1420218 Hom.: 3234 AF XY: 0.0545 AC XY: 38671 AN XY: 709090

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0309

Gnomad4 EAS exome AF: 0.0497

Gnomad4 SAS exome AF: 0.0410

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0663

GnomAD4 genome AF: 0.100 AC: 15209 AN: 151928 Hom.: 1203 Cov.: 31 AF XY: 0.100 AC XY: 7448 AN XY: 74258

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.0509

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.0504

Gnomad4 NFE AF: 0.0445

Gnomad4 OTH AF: 0.0924

Alfa AF: 0.0629 Hom.: 263

Bravo AF: 0.113

Asia WGS AF: 0.0720 AC: 250 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.86
CADD	Benign	0.36
DANN	Benign	0.50

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: rs2960336; hg19: chr19-39002140; COSMIC: COSV62098967; COSMIC: COSV62098967;