NM_000540.3:c.8400+61C>T

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.8400+61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,224,474 control chromosomes in the GnomAD database, including 1,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 700 hom., cov: 31)

Exomes 𝑓: 0.033 ( 989 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.262

Publications

3 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=-0.87).

BP6

Variant 19-38505459-C-T is Benign according to our data. Variant chr19-38505459-C-T is described in ClinVar as Benign. ClinVar VariationId is 133225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.8400+61C>T		intron_variant	Intron 53 of 105	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.8400+61C>T		intron_variant	Intron 53 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0689

AC:

10482

AN:

152100

Hom.:

696

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0711

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.00913

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0618

GnomAD4 exome

AF:

0.0333

AC:

35750

AN:

1072256

Hom.:

989

AF XY:

0.0322

AC XY:

17511

AN XY:

543944

show subpopulations

African (AFR)

AF:

0.164

AC:

4097

AN:

25004

American (AMR)

AF:

0.0885

AC:

3180

AN:

35938

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

665

AN:

23250

East Asian (EAS)

AF:

0.0000863

AC:

AN:

34754

South Asian (SAS)

AF:

0.0205

AC:

1500

AN:

73198

European-Finnish (FIN)

AF:

0.0135

AC:

659

AN:

48866

Middle Eastern (MID)

AF:

0.0284

AC:

140

AN:

4928

European-Non Finnish (NFE)

AF:

0.0303

AC:

23606

AN:

778994

Other (OTH)

AF:

0.0401

AC:

1900

AN:

47324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1515

3030

4544

6059

7574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.0691

AC:

10522

AN:

152218

Hom.:

700

Cov.:

AF XY:

0.0671

AC XY:

4998

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.168

AC:

6973

AN:

41510

American (AMR)

AF:

0.0714

AC:

1091

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5188

South Asian (SAS)

AF:

0.0199

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00913

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0298

AC:

2029

AN:

68006

Other (OTH)

AF:

0.0611

AC:

129

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

468

937

1405

1874

2342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0519

Hom.:

Bravo

AF:

0.0799

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.3

(source)

DANN

Benign

0.53

PhyloP100

-0.26

Mutation Taster

=98/2

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