19-38506683-T-C

Variant names:

• chr19-38506683-T-C
• rs2915957
• NM_000540.3:c.8692+137T>C

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.8692+137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,474,534 control chromosomes in the GnomAD database, including 60,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8631 hom., cov: 31)
  • Exomes 𝑓: 0.27 (51745 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.994
• Publications: 6 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=-0.87).
• BP6: Variant 19-38506683-T-C is Benign according to our data. Variant chr19-38506683-T-C is described in ClinVar as Benign. ClinVar VariationId is 590617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8692+137T>C		intron_variant	Intron 56 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8692+137T>C		intron_variant	Intron 56 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49473 AN: 151858 Hom.: 8595 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.271 AC: 358585 AN: 1322558 Hom.: 51745 Cov.: 21 AF XY: 0.276 AC XY: 182048 AN XY: 659430

African (AFR) AF: 0.428 AC: 12949 AN: 30282

American (AMR) AF: 0.380 AC: 14075 AN: 37020

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6214 AN: 24824

East Asian (EAS) AF: 0.334 AC: 12421 AN: 37204

South Asian (SAS) AF: 0.444 AC: 35513 AN: 79946

European-Finnish (FIN) AF: 0.289 AC: 14126 AN: 48942

Middle Eastern (MID) AF: 0.334 AC: 1838 AN: 5496

European-Non Finnish (NFE) AF: 0.245 AC: 245274 AN: 1003146

Other (OTH) AF: 0.290 AC: 16175 AN: 55698

GnomAD4 genome AF: 0.326 AC: 49570 AN: 151976 Hom.: 8631 Cov.: 31 AF XY: 0.333 AC XY: 24768 AN XY: 74290

African (AFR) AF: 0.431 AC: 17864 AN: 41438

American (AMR) AF: 0.355 AC: 5419 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3468

East Asian (EAS) AF: 0.362 AC: 1863 AN: 5144

South Asian (SAS) AF: 0.461 AC: 2218 AN: 4814

European-Finnish (FIN) AF: 0.289 AC: 3049 AN: 10566

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17223 AN: 67958

Other (OTH) AF: 0.338 AC: 714 AN: 2114

Alfa AF: 0.171 Hom.: 349

Bravo AF: 0.333

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 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

Apr 03, 2018

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	-0.87
CADD	Benign	5.4
DANN	Benign	0.72
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2915957; hg19: chr19-38997323; COSMIC: COSV62092643; COSMIC: COSV62092643;