NM_000540.3:c.2167+31C>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.2167+31C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,603,514 control chromosomes in the GnomAD database, including 33,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2522 hom., cov: 31)

Exomes 𝑓: 0.20 ( 30835 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.168

Publications

8 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=-0.72).

BP6

Variant 19-38458323-C-G is Benign according to our data. Variant chr19-38458323-C-G is described in ClinVar as Benign. ClinVar VariationId is 133112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.2167+31C>G		intron_variant	Intron 18 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.2167+31C>G		intron_variant	Intron 18 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25484

AN:

151984

Hom.:

2524

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0787

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.177

Gnomad EAS

AF:

0.363

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.209

AC:

51225

AN:

244530

AF XY:

0.212

show subpopulations

Gnomad AFR exome

AF:

0.0765

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.361

Gnomad FIN exome

AF:

0.209

Gnomad NFE exome

AF:

0.193

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.202

AC:

292883

AN:

1451412

Hom.:

30835

Cov.:

AF XY:

0.203

AC XY:

146978

AN XY:

722690

show subpopulations

African (AFR)

AF:

0.0699

AC:

2328

AN:

33304

American (AMR)

AF:

0.199

AC:

8903

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4875

AN:

26062

East Asian (EAS)

AF:

0.314

AC:

12465

AN:

39646

South Asian (SAS)

AF:

0.261

AC:

22474

AN:

86026

European-Finnish (FIN)

AF:

0.211

AC:

11118

AN:

52578

Middle Eastern (MID)

AF:

0.158

AC:

907

AN:

5750

European-Non Finnish (NFE)

AF:

0.198

AC:

217970

AN:

1103276

Other (OTH)

AF:

0.197

AC:

11843

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

11837

23674

35512

47349

59186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7840

15680

23520

31360

39200

<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:

0.168

AC:

25486

AN:

152102

Hom.:

2522

Cov.:

AF XY:

0.172

AC XY:

12813

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0787

AC:

3266

AN:

41516

American (AMR)

AF:

0.182

AC:

2786

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

615

AN:

3470

East Asian (EAS)

AF:

0.362

AC:

1861

AN:

5146

South Asian (SAS)

AF:

0.281

AC:

1354

AN:

4812

European-Finnish (FIN)

AF:

0.203

AC:

2154

AN:

10594

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.191

AC:

12956

AN:

67968

Other (OTH)

AF:

0.164

AC:

346

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1039

2078

3116

4155

5194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.179

Hom.:

459

Bravo

AF:

0.162

Asia WGS

AF:

0.348

AC:

1209

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Jun 19, 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. -

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

- -

not specified

Benign:1

Oct 18, 2013

PreventionGenetics, part of Exact Sciences

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

-0.72

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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