rs41274330

Variant names:

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.10218C>T(p.Tyr3406Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,601,676 control chromosomes in the GnomAD database, including 4,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 351 hom., cov: 31)

Exomes 𝑓: 0.060 ( 4170 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: -0.418

Publications

16 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=-0.39).

BP6

Variant 19-38519413-C-T is Benign according to our data. Variant chr19-38519413-C-T is described in ClinVar as Benign. ClinVar VariationId is 93240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.418 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 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.10218C>T	p.Tyr3406Tyr	synonymous	Exon 67 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10218C>T	p.Tyr3406Tyr	synonymous	Exon 67 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.10218C>T	p.Tyr3406Tyr	synonymous	Exon 67 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.10218C>T	p.Tyr3406Tyr	synonymous	Exon 67 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.*961C>T		non_coding_transcript_exon	Exon 66 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7175

AN:

152184

Hom.:

351

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0586

Gnomad ASJ

AF:

0.0602

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.223

Gnomad FIN

AF:

0.0164

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0482

Gnomad OTH

AF:

0.0502

GnomAD2 exomes

AF:

0.0759

AC:

17289

AN:

227876

AF XY:

0.0823

show subpopulations

Gnomad AFR exome

AF:

0.00957

Gnomad AMR exome

AF:

0.0633

Gnomad ASJ exome

AF:

0.0657

Gnomad EAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0489

Gnomad OTH exome

AF:

0.0714

GnomAD4 exome

AF:

0.0599

AC:

86745

AN:

1449374

Hom.:

4170

Cov.:

AF XY:

0.0643

AC XY:

46334

AN XY:

720214

show subpopulations

African (AFR)

AF:

0.0105

AC:

346

AN:

32996

American (AMR)

AF:

0.0622

AC:

2687

AN:

43208

Ashkenazi Jewish (ASJ)

AF:

0.0639

AC:

1655

AN:

25884

East Asian (EAS)

AF:

0.150

AC:

5792

AN:

38660

South Asian (SAS)

AF:

0.209

AC:

17689

AN:

84566

European-Finnish (FIN)

AF:

0.0208

AC:

1094

AN:

52670

Middle Eastern (MID)

AF:

0.0922

AC:

422

AN:

4576

European-Non Finnish (NFE)

AF:

0.0480

AC:

53156

AN:

1106992

Other (OTH)

AF:

0.0653

AC:

3904

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4778

9556

14333

19111

23889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2174

4348

6522

8696

10870

<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:

0.0471

AC:

7177

AN:

152302

Hom.:

351

Cov.:

AF XY:

0.0498

AC XY:

3711

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41574

American (AMR)

AF:

0.0583

AC:

892

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0602

AC:

209

AN:

3470

East Asian (EAS)

AF:

0.173

AC:

894

AN:

5166

South Asian (SAS)

AF:

0.223

AC:

1077

AN:

4828

European-Finnish (FIN)

AF:

0.0164

AC:

174

AN:

10620

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0482

AC:

3276

AN:

68022

Other (OTH)

AF:

0.0563

AC:

119

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

329

657

986

1314

1643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0456

Hom.:

145

Bravo

AF:

0.0447

Asia WGS

AF:

0.223

AC:

773

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)

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

-0.39

CADD

Benign

5.0

(source)

DANN

Benign

0.53

PhyloP100

-0.42

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