chr19-38505426-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BA1BP7

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.8400+28A>G in RYR1 is an intronic variant located in intron 53. The filtering allele frequency (the lower threshold of the 95% CI of 37922/85572, 8751 homozygotes) of the c.8400+28A>G variant in RYR1 is 0.4383 for South Asian chromosomes by gnomAD v4.1, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.00697) for BA1, and therefore meets this criterion (BA1). The c.8400+28A>G variant is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024918/MONDO:0100150/179

Frequency

Genomes: 𝑓 0.33 ( 8637 hom., cov: 31)

Exomes 𝑓: 0.27 ( 53110 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: 0.874

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), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
RYR1-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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 -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.8400+28A>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8400+28A>G		intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8400+28A>G	intron	N/A	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.8400+28A>G	intron	N/A	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.8400+28A>G	intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49483

AN:

151922

Hom.:

8602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.362

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.314

AC:

63093

AN:

200948

AF XY:

0.314

show subpopulations

Gnomad AFR exome

AF:

0.419

Gnomad AMR exome

AF:

0.382

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.271

AC:

367589

AN:

1356708

Hom.:

53110

Cov.:

AF XY:

0.276

AC XY:

186516

AN XY:

676690

show subpopulations

African (AFR)

AF:

0.428

AC:

13249

AN:

30952

American (AMR)

AF:

0.378

AC:

15162

AN:

40158

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

6284

AN:

25106

East Asian (EAS)

AF:

0.333

AC:

12673

AN:

38026

South Asian (SAS)

AF:

0.442

AC:

35712

AN:

80776

European-Finnish (FIN)

AF:

0.290

AC:

14814

AN:

51102

Middle Eastern (MID)

AF:

0.332

AC:

1799

AN:

5418

European-Non Finnish (NFE)

AF:

0.244

AC:

251442

AN:

1028528

Other (OTH)

AF:

0.290

AC:

16454

AN:

56642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

11300

22601

33901

45202

56502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8570

17140

25710

34280

42850

<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:

0.326

AC:

49579

AN:

152040

Hom.:

8637

Cov.:

AF XY:

0.333

AC XY:

24760

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.431

AC:

17870

AN:

41442

American (AMR)

AF:

0.355

AC:

5426

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

893

AN:

3472

East Asian (EAS)

AF:

0.361

AC:

1866

AN:

5162

South Asian (SAS)

AF:

0.461

AC:

2210

AN:

4796

European-Finnish (FIN)

AF:

0.289

AC:

3058

AN:

10584

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.253

AC:

17216

AN:

67998

Other (OTH)

AF:

0.338

AC:

715

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1696

3392

5088

6784

8480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<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:

0.283

Hom.:

4194

Bravo

AF:

0.333

Asia WGS

AF:

0.487

AC:

1691

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Central core myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (1)

King Denborough syndrome (1)

not specified (1)

RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

9.1

(source)

DANN

Benign

0.77

PhyloP100

0.87

Mutation Taster

=32/68

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over