19-38500960-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.7584C>T(p.Pro2528Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,613,114 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2528P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 211 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -4.93

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 19-38500960-C-T is Benign according to our data. Variant chr19-38500960-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.93 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.7584C>T	p.Pro2528Pro	synonymous_variant	Exon 47 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.7584C>T	p.Pro2528Pro	synonymous_variant	Exon 47 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1854

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0391

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.0679

Gnomad SAS

AF:

0.0270

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0155

AC:

3811

AN:

245820

AF XY:

0.0139

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0602

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.000764

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.00572

AC:

8354

AN:

1460870

Hom.:

211

Cov.:

AF XY:

0.00602

AC XY:

4378

AN XY:

726706

show subpopulations

African (AFR)

AF:

0.0157

AC:

526

AN:

33464

American (AMR)

AF:

0.0418

AC:

1868

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

270

AN:

26104

East Asian (EAS)

AF:

0.0733

AC:

2908

AN:

39680

South Asian (SAS)

AF:

0.0211

AC:

1817

AN:

86142

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

52920

Middle Eastern (MID)

AF:

0.00317

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.000351

AC:

390

AN:

1111890

Other (OTH)

AF:

0.00890

AC:

537

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

583

1166

1748

2331

2914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.0122

AC:

1854

AN:

152244

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1023

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0163

AC:

676

AN:

41540

American (AMR)

AF:

0.0388

AC:

594

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.0679

AC:

352

AN:

5186

South Asian (SAS)

AF:

0.0266

AC:

128

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68008

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

179

269

358

448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00502

Hom.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.0560

AC:

194

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

May 31, 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. -

Apr 22, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

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. -

Sep 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

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 03, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

-0.58

CADD

Benign

1.5

(source)

DANN

Benign

0.66

PhyloP100

-4.9

Mutation Taster

=96/4

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