19-38519383-C-T

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.10188C>T(p.Asp3396Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,605,854 control chromosomes in the GnomAD database, including 1,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 199 hom., cov: 31)

Exomes 𝑓: 0.042 ( 1530 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.58

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 19-38519383-C-T is Benign according to our data. Variant chr19-38519383-C-T is described in ClinVar as Benign. ClinVar VariationId is 93239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.58 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0627 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.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.10188C>T	p.Asp3396Asp	synonymous	Exon 67 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*931C>T		non_coding_transcript_exon	Exon 66 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.0416

AC:

6330

AN:

152176

Hom.:

199

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0403

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0487

GnomAD2 exomes

AF:

0.0444

AC:

10363

AN:

233166

AF XY:

0.0446

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0744

Gnomad EAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0498

Gnomad OTH exome

AF:

0.0553

GnomAD4 exome

AF:

0.0421

AC:

61154

AN:

1453560

Hom.:

1530

Cov.:

AF XY:

0.0422

AC XY:

30469

AN XY:

722606

show subpopulations

African (AFR)

AF:

0.0127

AC:

422

AN:

33228

American (AMR)

AF:

0.0281

AC:

1223

AN:

43460

Ashkenazi Jewish (ASJ)

AF:

0.0772

AC:

2002

AN:

25928

East Asian (EAS)

AF:

0.000153

AC:

AN:

39150

South Asian (SAS)

AF:

0.0237

AC:

2023

AN:

85298

European-Finnish (FIN)

AF:

0.115

AC:

6072

AN:

52846

Middle Eastern (MID)

AF:

0.0686

AC:

350

AN:

5102

European-Non Finnish (NFE)

AF:

0.0419

AC:

46416

AN:

1108534

Other (OTH)

AF:

0.0440

AC:

2640

AN:

60014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3569

7138

10707

14276

17845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1590

3180

4770

6360

7950

<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:

0.0416

AC:

6329

AN:

152294

Hom.:

199

Cov.:

AF XY:

0.0450

AC XY:

3348

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0130

AC:

540

AN:

41572

American (AMR)

AF:

0.0402

AC:

615

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0244

AC:

118

AN:

4832

European-Finnish (FIN)

AF:

0.118

AC:

1254

AN:

10604

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3387

AN:

68016

Other (OTH)

AF:

0.0477

AC:

101

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

296

592

887

1183

1479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0434

Hom.:

332

Bravo

AF:

0.0355

Asia WGS

AF:

0.0140

AC:

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)

not provided (4)

Malignant hyperthermia, susceptibility to, 1 (2)

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

-0.50

CADD

Benign

0.25

(source)

DANN

Benign

0.70

PhyloP100

-1.6

Mutation Taster

=99/1

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