19-38433722-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The NM_000540.3:c.-108T>C variant is located in exon 1 (5’ UTR) of the RYR1 gene. The filtering allele frequency (the lower threshold of the 95% CI of 8126/59394, 618 homozygotes) of the c.-108T>C variant in RYR1 is 0.1297 for African/African American 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). This variant is not predicted to impact splicing by SpliceAI. In addition, it occurs at a nucleotide that is poorly conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, the variant meets the criteria to be classified as benign for RYR1-related myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023868/MONDO:0100150/179

Frequency

Genomes: 𝑓 0.042 ( 431 hom., cov: 31)

Exomes 𝑓: 0.0085 ( 253 hom. )

Consequence

RYR1
NM_000540.3 5_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: -0.450

Publications

6 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.-108T>C		5_prime_UTR	Exon 1 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.-108T>C		5_prime_UTR	Exon 1 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.-108T>C	5_prime_UTR	Exon 1 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.-108T>C	5_prime_UTR	Exon 1 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.-108T>C	non_coding_transcript_exon	Exon 1 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6296

AN:

151926

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.0369

GnomAD4 exome

AF:

0.00855

AC:

5607

AN:

656068

Hom.:

253

Cov.:

AF XY:

0.00861

AC XY:

3007

AN XY:

349116

show subpopulations

African (AFR)

AF:

0.134

AC:

2410

AN:

17958

American (AMR)

AF:

0.00997

AC:

354

AN:

35518

Ashkenazi Jewish (ASJ)

AF:

0.000195

AC:

AN:

20538

East Asian (EAS)

AF:

0.00183

AC:

AN:

33844

South Asian (SAS)

AF:

0.0228

AC:

1487

AN:

65096

European-Finnish (FIN)

AF:

0.0000762

AC:

AN:

39378

Middle Eastern (MID)

AF:

0.00789

AC:

AN:

2660

European-Non Finnish (NFE)

AF:

0.00206

AC:

841

AN:

407424

Other (OTH)

AF:

0.0126

AC:

425

AN:

33652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

285

569

854

1138

1423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0416

AC:

6330

AN:

152038

Hom.:

431

Cov.:

AF XY:

0.0406

AC XY:

3018

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.138

AC:

5716

AN:

41436

American (AMR)

AF:

0.0174

AC:

265

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00175

AC:

AN:

5146

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00206

AC:

140

AN:

67984

Other (OTH)

AF:

0.0374

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

260

521

781

1042

1302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0179

Hom.:

149

Bravo

AF:

0.0464

Asia WGS

AF:

0.0350

AC:

121

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)

Malignant hyperthermia, susceptibility to, 1 (1)

Neuromuscular disease, congenital, with uniform type 1 fiber (1)

RYR1-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.4

(source)

DANN

Benign

0.68

PhyloP100

-0.45

PromoterAI

0.10

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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