rs35959206

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.13671C>G(p.Ser4557Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,262 control chromosomes in the GnomAD database, including 1,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 204 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1612 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.14

Publications

9 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=-0.66).

BP6

Variant 19-38570618-C-G is Benign according to our data. Variant chr19-38570618-C-G is described in ClinVar as Benign. ClinVar VariationId is 93253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.14 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.07 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.13671C>G	p.Ser4557Ser	synonymous	Exon 94 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.13656C>G	p.Ser4552Ser	synonymous	Exon 93 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.13671C>G	p.Ser4557Ser	synonymous	Exon 94 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.13656C>G	p.Ser4552Ser	synonymous	Exon 93 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.*4381C>G		non_coding_transcript_exon	Exon 91 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0419

AC:

6369

AN:

152094

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0404

Gnomad ASJ

AF:

0.0757

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0365

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0507

Gnomad OTH

AF:

0.0502

GnomAD2 exomes

AF:

0.0462

AC:

11620

AN:

251466

AF XY:

0.0470

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0265

Gnomad ASJ exome

AF:

0.0712

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0504

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0433

AC:

63241

AN:

1461050

Hom.:

1612

Cov.:

AF XY:

0.0437

AC XY:

31794

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.0118

AC:

395

AN:

33472

American (AMR)

AF:

0.0284

AC:

1271

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0740

AC:

1933

AN:

26124

East Asian (EAS)

AF:

0.000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0377

AC:

3252

AN:

86248

European-Finnish (FIN)

AF:

0.112

AC:

5981

AN:

53392

Middle Eastern (MID)

AF:

0.0758

AC:

436

AN:

5750

European-Non Finnish (NFE)

AF:

0.0425

AC:

47205

AN:

1111298

Other (OTH)

AF:

0.0457

AC:

2758

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

2937

5874

8812

11749

14686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1628

3256

4884

6512

8140

<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:

0.0418

AC:

6366

AN:

152212

Hom.:

204

Cov.:

AF XY:

0.0453

AC XY:

3369

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0114

AC:

474

AN:

41552

American (AMR)

AF:

0.0403

AC:

616

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0757

AC:

263

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.0367

AC:

177

AN:

4818

European-Finnish (FIN)

AF:

0.117

AC:

1242

AN:

10596

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0507

AC:

3446

AN:

68012

Other (OTH)

AF:

0.0492

AC:

104

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0487

Hom.:

Bravo

AF:

0.0353

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0551

EpiControl

AF:

0.0531

ClinVar

ClinVar submissions

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

-0.66

CADD

Benign

1.3

(source)

DANN

Benign

0.55

PhyloP100

-3.1

Mutation Taster

=96/4

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