NM_000540.3:c.7323+20C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000540.3(RYR1):c.7323+20C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0568 in 1,609,466 control chromosomes in the GnomAD database, including 3,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 374 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2671 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.0980

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 19-38500036-C-A is Benign according to our data. Variant chr19-38500036-C-A is described in ClinVar as Benign. ClinVar VariationId is 93286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 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.7323+20C>A		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7323+20C>A		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.7323+20C>A	intron	N/A	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.7323+20C>A	intron	N/A	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.7323+20C>A	intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0665

AC:

10124

AN:

152152

Hom.:

372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0658

Gnomad ASJ

AF:

0.0956

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.0552

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0575

Gnomad OTH

AF:

0.0750

GnomAD2 exomes

AF:

0.0693

AC:

17315

AN:

249882

AF XY:

0.0688

show subpopulations

Gnomad AFR exome

AF:

0.0610

Gnomad AMR exome

AF:

0.0468

Gnomad ASJ exome

AF:

0.0918

Gnomad EAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0800

GnomAD4 exome

AF:

0.0558

AC:

81351

AN:

1457196

Hom.:

2671

Cov.:

AF XY:

0.0564

AC XY:

40888

AN XY:

725192

show subpopulations

African (AFR)

AF:

0.0596

AC:

1989

AN:

33382

American (AMR)

AF:

0.0497

AC:

2220

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0949

AC:

2477

AN:

26104

East Asian (EAS)

AF:

0.125

AC:

4971

AN:

39672

South Asian (SAS)

AF:

0.0549

AC:

4726

AN:

86158

European-Finnish (FIN)

AF:

0.120

AC:

6374

AN:

53088

Middle Eastern (MID)

AF:

0.0954

AC:

548

AN:

5742

European-Non Finnish (NFE)

AF:

0.0489

AC:

54210

AN:

1108116

Other (OTH)

AF:

0.0637

AC:

3836

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3942

7883

11825

15766

19708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2002

4004

6006

8008

10010

<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:

0.0665

AC:

10127

AN:

152270

Hom.:

374

Cov.:

AF XY:

0.0705

AC XY:

5246

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0579

AC:

2408

AN:

41562

American (AMR)

AF:

0.0655

AC:

1003

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0956

AC:

332

AN:

3472

East Asian (EAS)

AF:

0.140

AC:

722

AN:

5162

South Asian (SAS)

AF:

0.0553

AC:

267

AN:

4830

European-Finnish (FIN)

AF:

0.122

AC:

1292

AN:

10606

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0574

AC:

3906

AN:

68014

Other (OTH)

AF:

0.0738

AC:

156

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

495

989

1484

1978

2473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0461

Hom.:

Bravo

AF:

0.0631

Asia WGS

AF:

0.0980

AC:

339

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.0

(source)

DANN

Benign

0.55

PhyloP100

-0.098

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