19-38499696-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.7089C>T(p.Cys2363Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,600,574 control chromosomes in the GnomAD database, including 2,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 363 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2560 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:12O:1

Conservation

PhyloP100: 0.339

Publications

10 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 19-38499696-C-T is Benign according to our data. Variant chr19-38499696-C-T is described in ClinVar as Benign. ClinVar VariationId is 93284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.339 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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.7089C>T	p.Cys2363Cys	synonymous	Exon 44 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7089C>T	p.Cys2363Cys	synonymous	Exon 44 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7089C>T	p.Cys2363Cys	synonymous	Exon 44 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.7089C>T	p.Cys2363Cys	synonymous	Exon 44 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.7089C>T		non_coding_transcript_exon	Exon 44 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0664

AC:

10095

AN:

152058

Hom.:

361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0657

Gnomad ASJ

AF:

0.0951

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.0550

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.0828

Gnomad NFE

AF:

0.0575

Gnomad OTH

AF:

0.0748

GnomAD2 exomes

AF:

0.0677

AC:

16176

AN:

238894

AF XY:

0.0677

show subpopulations

Gnomad AFR exome

AF:

0.0613

Gnomad AMR exome

AF:

0.0468

Gnomad ASJ exome

AF:

0.0919

Gnomad EAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0570

Gnomad OTH exome

AF:

0.0813

GnomAD4 exome

AF:

0.0553

AC:

80027

AN:

1448398

Hom.:

2560

Cov.:

AF XY:

0.0559

AC XY:

40277

AN XY:

720974

show subpopulations

African (AFR)

AF:

0.0592

AC:

1978

AN:

33440

American (AMR)

AF:

0.0496

AC:

2216

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0949

AC:

2478

AN:

26108

East Asian (EAS)

AF:

0.126

AC:

4989

AN:

39674

South Asian (SAS)

AF:

0.0549

AC:

4726

AN:

86068

European-Finnish (FIN)

AF:

0.119

AC:

4919

AN:

41498

Middle Eastern (MID)

AF:

0.0969

AC:

490

AN:

5056

European-Non Finnish (NFE)

AF:

0.0489

AC:

54408

AN:

1111718

Other (OTH)

AF:

0.0635

AC:

3823

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

4883

9765

14648

19530

24413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2014

4028

6042

8056

10070

<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:

0.0664

AC:

10098

AN:

152176

Hom.:

363

Cov.:

AF XY:

0.0702

AC XY:

5220

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0578

AC:

2399

AN:

41518

American (AMR)

AF:

0.0655

AC:

1002

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0951

AC:

330

AN:

3470

East Asian (EAS)

AF:

0.139

AC:

719

AN:

5170

South Asian (SAS)

AF:

0.0551

AC:

266

AN:

4828

European-Finnish (FIN)

AF:

0.120

AC:

1277

AN:

10606

Middle Eastern (MID)

AF:

0.0753

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0575

AC:

3909

AN:

67978

Other (OTH)

AF:

0.0735

AC:

155

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

456

912

1367

1823

2279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0615

Hom.:

263

Bravo

AF:

0.0631

Asia WGS

AF:

0.0990

AC:

344

AN:

3476

EpiCase

AF:

0.0617

EpiControl

AF:

0.0590

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Malignant hyperthermia, susceptibility to, 1 (2)

not provided (3)

Central core myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (1)

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

RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.3

(source)

DANN

Benign

0.76

PhyloP100

0.34

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over