NM_000540.3:c.8190T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000540.3(RYR1):c.8190T>C(p.Asp2730Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,742 control chromosomes in the GnomAD database, including 71,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9401 hom., cov: 31)

Exomes 𝑓: 0.28 ( 61784 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:18O:1

Conservation

PhyloP100: -2.91

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-38504870-T-C is Benign according to our data. Variant chr19-38504870-T-C is described in ClinVar as Benign. ClinVar VariationId is 93298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 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.8190T>C	p.Asp2730Asp	synonymous	Exon 51 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8190T>C	p.Asp2730Asp	synonymous	Exon 51 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.8190T>C	p.Asp2730Asp	synonymous	Exon 51 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.8190T>C	p.Asp2730Asp	synonymous	Exon 51 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.8190T>C		non_coding_transcript_exon	Exon 51 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51328

AN:

151784

Hom.:

9359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.360

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.328

AC:

82451

AN:

251402

AF XY:

0.327

show subpopulations

Gnomad AFR exome

AF:

0.471

Gnomad AMR exome

AF:

0.397

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.305

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.309

GnomAD4 exome

AF:

0.283

AC:

413487

AN:

1461840

Hom.:

61784

Cov.:

AF XY:

0.287

AC XY:

208797

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.465

AC:

15558

AN:

33480

American (AMR)

AF:

0.392

AC:

17517

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6913

AN:

26136

East Asian (EAS)

AF:

0.338

AC:

13408

AN:

39700

South Asian (SAS)

AF:

0.447

AC:

38542

AN:

86256

European-Finnish (FIN)

AF:

0.301

AC:

16100

AN:

53414

Middle Eastern (MID)

AF:

0.341

AC:

1967

AN:

5768

European-Non Finnish (NFE)

AF:

0.257

AC:

285256

AN:

1111972

Other (OTH)

AF:

0.302

AC:

18226

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

19898

39796

59695

79593

99491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9932

19864

29796

39728

49660

<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:

0.339

AC:

51429

AN:

151902

Hom.:

9401

Cov.:

AF XY:

0.345

AC XY:

25642

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.461

AC:

19078

AN:

41382

American (AMR)

AF:

0.361

AC:

5505

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

944

AN:

3472

East Asian (EAS)

AF:

0.360

AC:

1855

AN:

5148

South Asian (SAS)

AF:

0.460

AC:

2218

AN:

4820

European-Finnish (FIN)

AF:

0.299

AC:

3159

AN:

10562

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.259

AC:

17609

AN:

67934

Other (OTH)

AF:

0.346

AC:

730

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1687

3373

5060

6746

8433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.289

Hom.:

7686

Bravo

AF:

0.346

Asia WGS

AF:

0.490

AC:

1700

AN:

3478

EpiCase

AF:

0.269

EpiControl

AF:

0.271

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Central core myopathy (2)

Congenital multicore myopathy with external ophthalmoplegia (2)

Malignant hyperthermia, susceptibility to, 1 (2)

not provided (3)

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)

King Denborough syndrome (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

-0.83

CADD

Benign

0.13

(source)

DANN

Benign

0.46

PhyloP100

-2.9

Mutation Taster

=97/3

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