rs2915952

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.8337G>A(p.Glu2779Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,608,310 control chromosomes in the GnomAD database, including 67,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8646 hom., cov: 31)

Exomes 𝑓: 0.27 ( 58440 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.45

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 19-38505335-G-A is Benign according to our data. Variant chr19-38505335-G-A is described in ClinVar as Benign. ClinVar VariationId is 93299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 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.8337G>A	p.Glu2779Glu	synonymous	Exon 53 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8337G>A	p.Glu2779Glu	synonymous	Exon 53 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.8337G>A	p.Glu2779Glu	synonymous	Exon 53 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.8337G>A	p.Glu2779Glu	synonymous	Exon 53 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.8337G>A		non_coding_transcript_exon	Exon 53 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49470

AN:

151860

Hom.:

8610

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.261

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.362

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.315

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.319

AC:

78977

AN:

247926

AF XY:

0.318

show subpopulations

Gnomad AFR exome

AF:

0.434

Gnomad AMR exome

AF:

0.390

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.294

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.275

AC:

400045

AN:

1456332

Hom.:

58440

Cov.:

AF XY:

0.279

AC XY:

202266

AN XY:

724460

show subpopulations

African (AFR)

AF:

0.433

AC:

14429

AN:

33344

American (AMR)

AF:

0.386

AC:

17153

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

6544

AN:

26034

East Asian (EAS)

AF:

0.337

AC:

13384

AN:

39660

South Asian (SAS)

AF:

0.446

AC:

38204

AN:

85742

European-Finnish (FIN)

AF:

0.292

AC:

15554

AN:

53266

Middle Eastern (MID)

AF:

0.333

AC:

1824

AN:

5476

European-Non Finnish (NFE)

AF:

0.248

AC:

275315

AN:

1108204

Other (OTH)

AF:

0.293

AC:

17638

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

14774

29548

44322

59096

73870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9582

19164

28746

38328

47910

<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:

0.326

AC:

49567

AN:

151978

Hom.:

8646

Cov.:

AF XY:

0.333

AC XY:

24766

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.431

AC:

17864

AN:

41436

American (AMR)

AF:

0.356

AC:

5433

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

893

AN:

3472

East Asian (EAS)

AF:

0.361

AC:

1865

AN:

5162

South Asian (SAS)

AF:

0.460

AC:

2214

AN:

4808

European-Finnish (FIN)

AF:

0.290

AC:

3056

AN:

10552

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.253

AC:

17199

AN:

67962

Other (OTH)

AF:

0.338

AC:

715

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1663

3325

4988

6650

8313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

490

980

1470

1960

2450

<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:

0.285

Hom.:

5541

Bravo

AF:

0.333

Asia WGS

AF:

0.486

AC:

1689

AN:

3478

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

-0.43

CADD

Benign

4.6

(source)

DANN

Benign

0.52

PhyloP100

1.4

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