19-38501000-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000540.3(RYR1):c.7614+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,610,936 control chromosomes in the GnomAD database, including 29,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4562 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25122 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:16O:1

Conservation

PhyloP100: 0.348

Publications

9 publications found

Variant links:

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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 19-38501000-C-G is Benign according to our data. Variant chr19-38501000-C-G is described in ClinVar as Benign. ClinVar VariationId is 93289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.7614+10C>G		intron_variant	Intron 47 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.7614+10C>G		intron_variant	Intron 47 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35106

AN:

152002

Hom.:

4546

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.211

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.232

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.214

AC:

51936

AN:

242586

AF XY:

0.209

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.304

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.179

AC:

261471

AN:

1458818

Hom.:

25122

Cov.:

AF XY:

0.180

AC XY:

130547

AN XY:

725520

show subpopulations

African (AFR)

AF:

0.344

AC:

11494

AN:

33448

American (AMR)

AF:

0.298

AC:

13241

AN:

44418

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

4762

AN:

25990

East Asian (EAS)

AF:

0.199

AC:

7885

AN:

39672

South Asian (SAS)

AF:

0.215

AC:

18476

AN:

85856

European-Finnish (FIN)

AF:

0.234

AC:

12271

AN:

52480

Middle Eastern (MID)

AF:

0.205

AC:

1172

AN:

5714

European-Non Finnish (NFE)

AF:

0.162

AC:

180429

AN:

1110962

Other (OTH)

AF:

0.195

AC:

11741

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

11467

22934

34400

45867

57334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6620

13240

19860

26480

33100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.231

AC:

35156

AN:

152118

Hom.:

4562

Cov.:

AF XY:

0.235

AC XY:

17501

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.341

AC:

14123

AN:

41476

American (AMR)

AF:

0.254

AC:

3877

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

667

AN:

3472

East Asian (EAS)

AF:

0.211

AC:

1091

AN:

5170

South Asian (SAS)

AF:

0.218

AC:

1050

AN:

4822

European-Finnish (FIN)

AF:

0.232

AC:

2456

AN:

10588

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11316

AN:

67984

Other (OTH)

AF:

0.234

AC:

494

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1371

2742

4112

5483

6854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.125

Hom.:

281

Bravo

AF:

0.239

Asia WGS

AF:

0.249

AC:

867

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 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 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.7614+10C>G in intron 47 of RYR1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 33.2% (1463/4406) of African American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2960323). -

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 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. -

not provided

Uncertain:1Benign:1Other: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: 36.177% 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

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:2

Nov 07, 2021

Genome-Nilou Lab

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. -

Central core myopathy

Benign:2

Nov 07, 2021

Genome-Nilou Lab

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

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

- -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

-0.73

CADD

Benign

6.6

(source)

DANN

Benign

0.67

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over