19-38505980-C-T

Variant names:

• chr19-38505980-C-T
• rs2960342
• NM_000540.3:c.8541+34C>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.8541+34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,552,680 control chromosomes in the GnomAD database, including 65,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8405 hom., cov: 29)
  • Exomes 𝑓: 0.27 (56850 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.219
• Publications: 9 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=-0.94).
• BP6: Variant 19-38505980-C-T is Benign according to our data. Variant chr19-38505980-C-T is described in ClinVar as Benign. ClinVar VariationId is 133227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8541+34C>T		intron_variant	Intron 54 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8541+34C>T		intron_variant	Intron 54 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 48722 AN: 149882 Hom.: 8368 Cov.: 29

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.319 AC: 76408 AN: 239744 AF XY: 0.319

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.265 AC: 372072 AN: 1402678 Hom.: 56850 Cov.: 33 AF XY: 0.271 AC XY: 189274 AN XY: 699538

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.427 AC: 13660 AN: 31972

American (AMR) AF: 0.386 AC: 17090 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6389 AN: 25752

East Asian (EAS) AF: 0.336 AC: 13165 AN: 39234

South Asian (SAS) AF: 0.444 AC: 37377 AN: 84242

European-Finnish (FIN) AF: 0.289 AC: 14651 AN: 50720

Middle Eastern (MID) AF: 0.317 AC: 1464 AN: 4624

European-Non Finnish (NFE) AF: 0.237 AC: 251614 AN: 1063532

Other (OTH) AF: 0.286 AC: 16662 AN: 58352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.325 AC: 48821 AN: 150002 Hom.: 8405 Cov.: 29 AF XY: 0.333 AC XY: 24347 AN XY: 73166

African (AFR) AF: 0.431 AC: 17591 AN: 40790

American (AMR) AF: 0.354 AC: 5341 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 883 AN: 3446

East Asian (EAS) AF: 0.358 AC: 1805 AN: 5046

South Asian (SAS) AF: 0.460 AC: 2181 AN: 4744

European-Finnish (FIN) AF: 0.290 AC: 2972 AN: 10264

Middle Eastern (MID) AF: 0.310 AC: 90 AN: 290

European-Non Finnish (NFE) AF: 0.253 AC: 17019 AN: 67366

Other (OTH) AF: 0.338 AC: 704 AN: 2080

Alfa AF: 0.323 Hom.: 2372

Bravo AF: 0.332

Asia WGS AF: 0.483 AC: 1677 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

not specified Benign:1

Oct 25, 2013

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

King Denborough syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:1

Nov 07, 2021

Genome-Nilou Lab

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	-0.94
CADD	Benign	0.62
DANN	Benign	0.76
PhyloP100		-0.22
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: rs2960342; hg19: chr19-38996620; COSMIC: COSV62092761;