NM_000540.3:c.594A>G

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.594A>G(p.Leu198Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,612,584 control chromosomes in the GnomAD database, including 316,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28245 hom., cov: 29)

Exomes 𝑓: 0.63 ( 288583 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.221

Publications

28 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=-0.58).

BP6

Variant 19-38444640-A-G is Benign according to our data. Variant chr19-38444640-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.221 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.665 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.594A>G	p.Leu198Leu	synonymous	Exon 7 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.594A>G	p.Leu198Leu	synonymous	Exon 7 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.594A>G	p.Leu198Leu	synonymous	Exon 7 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.594A>G	p.Leu198Leu	synonymous	Exon 7 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.594A>G		non_coding_transcript_exon	Exon 7 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91574

AN:

151362

Hom.:

28238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.520

Gnomad AMI

AF:

0.748

Gnomad AMR

AF:

0.675

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.624

GnomAD2 exomes

AF:

0.609

AC:

152434

AN:

250168

AF XY:

0.602

show subpopulations

Gnomad AFR exome

AF:

0.514

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.617

Gnomad EAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.647

Gnomad NFE exome

AF:

0.645

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.625

AC:

913320

AN:

1461106

Hom.:

288583

Cov.:

AF XY:

0.619

AC XY:

449792

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.513

AC:

17173

AN:

33458

American (AMR)

AF:

0.678

AC:

30272

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.606

AC:

15839

AN:

26126

East Asian (EAS)

AF:

0.654

AC:

25948

AN:

39682

South Asian (SAS)

AF:

0.415

AC:

35747

AN:

86172

European-Finnish (FIN)

AF:

0.645

AC:

34442

AN:

53384

Middle Eastern (MID)

AF:

0.618

AC:

3562

AN:

5764

European-Non Finnish (NFE)

AF:

0.641

AC:

712677

AN:

1111506

Other (OTH)

AF:

0.624

AC:

37660

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

18539

37078

55616

74155

92694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18700

37400

56100

74800

93500

<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:

0.605

AC:

91614

AN:

151478

Hom.:

28245

Cov.:

AF XY:

0.600

AC XY:

44400

AN XY:

73964

show subpopulations

African (AFR)

AF:

0.519

AC:

21428

AN:

41250

American (AMR)

AF:

0.675

AC:

10276

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

2128

AN:

3466

East Asian (EAS)

AF:

0.625

AC:

3194

AN:

5112

South Asian (SAS)

AF:

0.403

AC:

1932

AN:

4796

European-Finnish (FIN)

AF:

0.653

AC:

6805

AN:

10426

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.643

AC:

43680

AN:

67908

Other (OTH)

AF:

0.618

AC:

1298

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1755

3510

5264

7019

8774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.619

Hom.:

19997

Bravo

AF:

0.609

Asia WGS

AF:

0.454

AC:

1580

AN:

3478

EpiCase

AF:

0.645

EpiControl

AF:

0.652

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Central core myopathy (2)

Congenital multicore myopathy with external ophthalmoplegia (2)

Malignant hyperthermia, susceptibility to, 1 (2)

King Denborough syndrome (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

-0.58

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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