chr19-38469040-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.3456C>T(p.Ile1152Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,670 control chromosomes in the GnomAD database, including 114,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1152I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.39 ( 11569 hom., cov: 31)

Exomes 𝑓: 0.37 ( 103147 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: -3.62

Publications

21 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=-0.31).

BP6

Variant 19-38469040-C-T is Benign according to our data. Variant chr19-38469040-C-T is described in ClinVar as Benign. ClinVar VariationId is 93263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.62 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.526 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.3456C>T	p.Ile1152Ile	synonymous	Exon 26 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.3456C>T	p.Ile1152Ile	synonymous	Exon 26 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.3456C>T	p.Ile1152Ile	synonymous	Exon 26 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.3456C>T	p.Ile1152Ile	synonymous	Exon 26 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.3456C>T		non_coding_transcript_exon	Exon 26 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58610

AN:

151858

Hom.:

11545

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.290

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.339

Gnomad EAS

AF:

0.466

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.293

Gnomad NFE

AF:

0.355

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.391

AC:

98237

AN:

251440

AF XY:

0.395

show subpopulations

Gnomad AFR exome

AF:

0.441

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.406

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.361

GnomAD4 exome

AF:

0.372

AC:

543190

AN:

1461694

Hom.:

103147

Cov.:

AF XY:

0.376

AC XY:

273642

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.435

AC:

14570

AN:

33474

American (AMR)

AF:

0.324

AC:

14481

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

9003

AN:

26136

East Asian (EAS)

AF:

0.408

AC:

16187

AN:

39700

South Asian (SAS)

AF:

0.523

AC:

45122

AN:

86248

European-Finnish (FIN)

AF:

0.404

AC:

21591

AN:

53410

Middle Eastern (MID)

AF:

0.341

AC:

1966

AN:

5768

European-Non Finnish (NFE)

AF:

0.358

AC:

398223

AN:

1111842

Other (OTH)

AF:

0.365

AC:

22047

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

20000

40000

59999

79999

99999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12872

25744

38616

51488

64360

<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:

0.386

AC:

58678

AN:

151976

Hom.:

11569

Cov.:

AF XY:

0.392

AC XY:

29091

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.434

AC:

17988

AN:

41422

American (AMR)

AF:

0.326

AC:

4971

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.339

AC:

1178

AN:

3472

East Asian (EAS)

AF:

0.465

AC:

2397

AN:

5154

South Asian (SAS)

AF:

0.543

AC:

2613

AN:

4812

European-Finnish (FIN)

AF:

0.404

AC:

4269

AN:

10562

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.355

AC:

24116

AN:

67980

Other (OTH)

AF:

0.376

AC:

794

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1820

3640

5461

7281

9101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.364

Hom.:

42201

Bravo

AF:

0.378

Asia WGS

AF:

0.548

AC:

1903

AN:

3478

EpiCase

AF:

0.351

EpiControl

AF:

0.345

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Malignant hyperthermia, susceptibility to, 1 (2)

Central core myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (1)

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

not provided (2)

RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

5.6

(source)

DANN

Benign

0.82

PhyloP100

-3.6

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