19-38586613-G-T

Variant names:

• chr19-38586613-G-T
• rs73032657
• NM_000540.3:c.15021+37G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.15021+37G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0802 in 1,593,966 control chromosomes in the GnomAD database, including 5,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (401 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5517 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.96
• Publications: 4 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-38586613-G-T is Benign according to our data. Variant chr19-38586613-G-T is described in ClinVar as [Benign]. Clinvar id is 256455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.15021+37G>T		intron_variant	Intron 105 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.15021+37G>T		intron_variant	Intron 105 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9255 AN: 152098 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0621 AC: 15610 AN: 251190 AF XY: 0.0629

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0823 AC: 118620 AN: 1441750 Hom.: 5517 Cov.: 27 AF XY: 0.0810 AC XY: 58209 AN XY: 718586

African (AFR) AF: 0.0116 AC: 383 AN: 33076

American (AMR) AF: 0.0303 AC: 1356 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 714 AN: 26016

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39602

South Asian (SAS) AF: 0.0344 AC: 2956 AN: 85842

European-Finnish (FIN) AF: 0.117 AC: 6271 AN: 53384

Middle Eastern (MID) AF: 0.0236 AC: 135 AN: 5730

European-Non Finnish (NFE) AF: 0.0938 AC: 102596 AN: 1093744

Other (OTH) AF: 0.0704 AC: 4202 AN: 59676

GnomAD4 genome AF: 0.0608 AC: 9253 AN: 152216 Hom.: 401 Cov.: 32 AF XY: 0.0595 AC XY: 4431 AN XY: 74414

African (AFR) AF: 0.0150 AC: 623 AN: 41542

American (AMR) AF: 0.0359 AC: 549 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0310 AC: 150 AN: 4832

European-Finnish (FIN) AF: 0.117 AC: 1244 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0923 AC: 6274 AN: 67998

Other (OTH) AF: 0.0492 AC: 104 AN: 2112

Alfa AF: 0.0742 Hom.: 361

Bravo AF: 0.0537

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Oct 30, 2013

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.013
DANN	Benign	0.44
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73032657; hg19: chr19-39077253;