19-38504715-ACCT-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000540.3(RYR1):c.8068-29_8068-27delCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,611,506 control chromosomes in the GnomAD database, including 68,568 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9153 hom., cov: 0)

Exomes 𝑓: 0.28 ( 59415 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.613

Publications

3 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 -16 ACMG points.

BP6

Variant 19-38504715-ACCT-A is Benign according to our data. Variant chr19-38504715-ACCT-A is described in ClinVar as Benign. ClinVar VariationId is 256570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.8068-29_8068-27delCCT		intron_variant	Intron 50 of 105	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.8068-32_8068-30delCCT		intron_variant	Intron 50 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50542

AN:

151246

Hom.:

9111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.459

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.360

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.340

GnomAD2 exomes

AF:

0.324

AC:

81212

AN:

250880

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.469

Gnomad AMR exome

AF:

0.395

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.339

Gnomad FIN exome

AF:

0.295

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.277

AC:

403925

AN:

1460142

Hom.:

59415

AF XY:

0.281

AC XY:

204139

AN XY:

726388

show subpopulations

African (AFR)

AF:

0.463

AC:

15485

AN:

33424

American (AMR)

AF:

0.390

AC:

17451

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

6844

AN:

26132

East Asian (EAS)

AF:

0.338

AC:

13394

AN:

39682

South Asian (SAS)

AF:

0.447

AC:

38471

AN:

86152

European-Finnish (FIN)

AF:

0.292

AC:

15582

AN:

53324

Middle Eastern (MID)

AF:

0.331

AC:

1733

AN:

5236

European-Non Finnish (NFE)

AF:

0.249

AC:

277090

AN:

1111200

Other (OTH)

AF:

0.296

AC:

17875

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

15389

30777

46166

61554

76943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9670

19340

29010

38680

48350

<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:

0.335

AC:

50643

AN:

151364

Hom.:

9153

Cov.:

AF XY:

0.341

AC XY:

25216

AN XY:

73908

show subpopulations

African (AFR)

AF:

0.460

AC:

18964

AN:

41194

American (AMR)

AF:

0.358

AC:

5439

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

933

AN:

3468

East Asian (EAS)

AF:

0.359

AC:

1835

AN:

5106

South Asian (SAS)

AF:

0.461

AC:

2209

AN:

4796

European-Finnish (FIN)

AF:

0.289

AC:

3025

AN:

10466

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.253

AC:

17187

AN:

67840

Other (OTH)

AF:

0.345

AC:

722

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1622

3244

4866

6488

8110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.281

Hom.:

1166

Bravo

AF:

0.343

Asia WGS

AF:

0.490

AC:

1701

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 25, 2013

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

King Denborough syndrome

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.61

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over