rs5828009

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.8932+34dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8550 hom., cov: 0)

Exomes 𝑓: 0.27 ( 49339 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.483

Publications

7 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 19-38507857-G-GC is Benign according to our data. Variant chr19-38507857-G-GC is described in ClinVar as Benign. ClinVar VariationId is 256576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.8932+34dupC		intron_variant	Intron 58 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.8932+30_8932+31insC		intron_variant	Intron 58 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

49168

AN:

151454

Hom.:

8514

Cov.:

show subpopulations

Gnomad AFR

AF:

0.428

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.322

AC:

80321

AN:

249778

AF XY:

0.322

show subpopulations

Gnomad AFR exome

AF:

0.437

Gnomad AMR exome

AF:

0.393

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.296

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.305

GnomAD4 exome

AF:

0.270

AC:

329869

AN:

1223892

Hom.:

49339

Cov.:

AF XY:

0.276

AC XY:

171019

AN XY:

620590

show subpopulations

African (AFR)

AF:

0.425

AC:

12074

AN:

28392

American (AMR)

AF:

0.387

AC:

17119

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

6125

AN:

24650

East Asian (EAS)

AF:

0.336

AC:

12880

AN:

38384

South Asian (SAS)

AF:

0.444

AC:

35944

AN:

80980

European-Finnish (FIN)

AF:

0.292

AC:

15477

AN:

52996

Middle Eastern (MID)

AF:

0.328

AC:

1716

AN:

5230

European-Non Finnish (NFE)

AF:

0.238

AC:

213433

AN:

896568

Other (OTH)

AF:

0.288

AC:

15101

AN:

52444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

10202

20404

30606

40808

51010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6646

13292

19938

26584

33230

<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:

0.325

AC:

49265

AN:

151572

Hom.:

8550

Cov.:

AF XY:

0.332

AC XY:

24565

AN XY:

74008

show subpopulations

African (AFR)

AF:

0.429

AC:

17680

AN:

41236

American (AMR)

AF:

0.355

AC:

5417

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

889

AN:

3468

East Asian (EAS)

AF:

0.360

AC:

1846

AN:

5126

South Asian (SAS)

AF:

0.460

AC:

2208

AN:

4800

European-Finnish (FIN)

AF:

0.286

AC:

3005

AN:

10490

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.253

AC:

17181

AN:

67900

Other (OTH)

AF:

0.338

AC:

710

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1537

3074

4611

6148

7685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

488

976

1464

1952

2440

<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:

0.275

Hom.:

1092

Bravo

AF:

0.331

Asia WGS

AF:

0.487

AC:

1692

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 28, 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

Oct 27, 2018

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

-0.48

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