19-38502732-A-G

Variant names:

• chr19-38502732-A-G
• rs1469695
• NM_000540.3:c.7835+5A>G

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.7835+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,416,812 control chromosomes in the GnomAD database, including 70,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (8710 hom., cov: 20)
  • Exomes 𝑓: 0.32 (61435 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004438
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:1
• Conservation: PhyloP100: 0.157
• Publications: 14 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=-0.92).
• BP6: Variant 19-38502732-A-G is Benign according to our data. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502732-A-G is described in CliVar as Benign. Clinvar id is 93292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7835+5A>G		splice_region_variant, intron_variant	Intron 48 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7835+5A>G		splice_region_variant, intron_variant	Intron 48 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 47409 AN: 122054 Hom.: 8680 Cov.: 20

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.335 AC: 76265 AN: 227728 AF XY: 0.333

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.344

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.316 AC: 408965 AN: 1294658 Hom.: 61435 Cov.: 38 AF XY: 0.320 AC XY: 206197 AN XY: 643496

African (AFR) AF: 0.476 AC: 14307 AN: 30034

American (AMR) AF: 0.463 AC: 19166 AN: 41410

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 6878 AN: 21092

East Asian (EAS) AF: 0.444 AC: 13140 AN: 29572

South Asian (SAS) AF: 0.450 AC: 37094 AN: 82400

European-Finnish (FIN) AF: 0.398 AC: 13264 AN: 33300

Middle Eastern (MID) AF: 0.376 AC: 1918 AN: 5102

European-Non Finnish (NFE) AF: 0.285 AC: 285202 AN: 1000208

Other (OTH) AF: 0.349 AC: 17996 AN: 51540

GnomAD4 genome AF: 0.389 AC: 47491 AN: 122154 Hom.: 8710 Cov.: 20 AF XY: 0.403 AC XY: 23373 AN XY: 57968

African (AFR) AF: 0.502 AC: 16938 AN: 33752

American (AMR) AF: 0.476 AC: 5416 AN: 11376

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 920 AN: 3026

East Asian (EAS) AF: 0.416 AC: 1571 AN: 3778

South Asian (SAS) AF: 0.508 AC: 1775 AN: 3496

European-Finnish (FIN) AF: 0.416 AC: 2858 AN: 6870

Middle Eastern (MID) AF: 0.374 AC: 86 AN: 230

European-Non Finnish (NFE) AF: 0.298 AC: 17047 AN: 57200

Other (OTH) AF: 0.401 AC: 660 AN: 1646

Alfa AF: 0.322 Hom.: 4026

Bravo AF: 0.351

Asia WGS AF: 0.458 AC: 1533 AN: 3356

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2016

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. -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.7835+5A>G in intron 48 of RYR1: This variant is not expected to have clinical significance because it has been identified in 44.2% (1949/4406) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs1469695). -

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 46.669% in ExAC) based on the frequency threshold of 2.223% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. 9 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Malignant hyperthermia, susceptibility to, 1 Benign:3

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.1
DANN	Benign	0.42
PhyloP100		0.16
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0020
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: rs1469695; hg19: chr19-38993372; COSMIC: COSV62089426;