rs2304151

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000540.3(RYR1):c.9690G>A(p.Leu3230Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,613,208 control chromosomes in the GnomAD database, including 4,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 394 hom., cov: 31)

Exomes 𝑓: 0.073 ( 4538 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.04

Publications

8 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), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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 -16 ACMG points.

BP6

Variant 19-38517363-G-A is Benign according to our data. Variant chr19-38517363-G-A is described in ClinVar as Benign. ClinVar VariationId is 93308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 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.9690G>A	p.Leu3230Leu	synonymous	Exon 66 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.9690G>A	p.Leu3230Leu	synonymous	Exon 66 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.9690G>A	p.Leu3230Leu	synonymous	Exon 66 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.9690G>A	p.Leu3230Leu	synonymous	Exon 66 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*433G>A		non_coding_transcript_exon	Exon 65 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.0628

AC:

9540

AN:

152002

Hom.:

393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0311

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.0930

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.0874

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0661

Gnomad OTH

AF:

0.0756

GnomAD2 exomes

AF:

0.0851

AC:

21056

AN:

247386

AF XY:

0.0887

show subpopulations

Gnomad AFR exome

AF:

0.0288

Gnomad AMR exome

AF:

0.0736

Gnomad ASJ exome

AF:

0.0806

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0859

Gnomad NFE exome

AF:

0.0692

Gnomad OTH exome

AF:

0.0760

GnomAD4 exome

AF:

0.0734

AC:

107222

AN:

1461088

Hom.:

4538

Cov.:

AF XY:

0.0762

AC XY:

55409

AN XY:

726884

show subpopulations

African (AFR)

AF:

0.0306

AC:

1025

AN:

33480

American (AMR)

AF:

0.0707

AC:

3161

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0828

AC:

2164

AN:

26132

East Asian (EAS)

AF:

0.132

AC:

5225

AN:

39700

South Asian (SAS)

AF:

0.154

AC:

13239

AN:

86238

European-Finnish (FIN)

AF:

0.0845

AC:

4468

AN:

52872

Middle Eastern (MID)

AF:

0.0987

AC:

557

AN:

5646

European-Non Finnish (NFE)

AF:

0.0656

AC:

72930

AN:

1111936

Other (OTH)

AF:

0.0738

AC:

4453

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6300

12601

18901

25202

31502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2794

5588

8382

11176

13970

<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:

0.0628

AC:

9546

AN:

152120

Hom.:

394

Cov.:

AF XY:

0.0657

AC XY:

4887

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0310

AC:

1287

AN:

41492

American (AMR)

AF:

0.0556

AC:

850

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0930

AC:

323

AN:

3472

East Asian (EAS)

AF:

0.136

AC:

704

AN:

5158

South Asian (SAS)

AF:

0.157

AC:

758

AN:

4814

European-Finnish (FIN)

AF:

0.0874

AC:

927

AN:

10606

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0662

AC:

4497

AN:

67976

Other (OTH)

AF:

0.0772

AC:

163

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

437

875

1312

1750

2187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0676

Hom.:

434

Bravo

AF:

0.0582

Asia WGS

AF:

0.143

AC:

494

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

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

-0.45

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 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