rs199849275

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000540.3(RYR1):c.7836-28dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,600,600 control chromosomes in the GnomAD database, including 267 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 29)

Exomes 𝑓: 0.014 ( 253 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.62

Publications

0 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 -10 ACMG points.

BP6

Variant 19-38502851-G-GA is Benign according to our data. Variant chr19-38502851-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 256561.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1653/151022) while in subpopulation NFE AF = 0.0172 (1162/67616). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 751 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR,AD gene

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.7836-28dupA		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7836-28dupA		intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7836-29_7836-28insA	intron	N/A	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.7836-29_7836-28insA	intron	N/A	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.7836-29_7836-28insA	intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1653

AN:

150908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.00337

Gnomad FIN

AF:

0.00803

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00918

AC:

2221

AN:

241952

AF XY:

0.00950

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.0136

AC:

19697

AN:

1449578

Hom.:

253

Cov.:

AF XY:

0.0134

AC XY:

9658

AN XY:

721456

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33412

American (AMR)

AF:

0.00944

AC:

421

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

348

AN:

26078

East Asian (EAS)

AF:

0.000101

AC:

AN:

39672

South Asian (SAS)

AF:

0.00309

AC:

265

AN:

85890

European-Finnish (FIN)

AF:

0.00876

AC:

407

AN:

46462

Middle Eastern (MID)

AF:

0.00560

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0157

AC:

17376

AN:

1107574

Other (OTH)

AF:

0.0128

AC:

772

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

1091

2182

3274

4365

5456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.0109

AC:

1653

AN:

151022

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

751

AN XY:

73756

show subpopulations

African (AFR)

AF:

0.00311

AC:

128

AN:

41180

American (AMR)

AF:

0.0116

AC:

176

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3460

East Asian (EAS)

AF:

0.000392

AC:

AN:

5100

South Asian (SAS)

AF:

0.00358

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00803

AC:

AN:

10460

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0172

AC:

1162

AN:

67616

Other (OTH)

AF:

0.0110

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00759

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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