19-38444726-C-T

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.631+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,416,604 control chromosomes in the GnomAD database, including 1,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 314 hom., cov: 28)

Exomes 𝑓: 0.044 ( 1526 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0210

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-38444726-C-T is Benign according to our data. Variant chr19-38444726-C-T is described in ClinVar as [Benign]. Clinvar id is 256532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.631+49C>T		intron_variant	Intron 7 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.631+49C>T		intron_variant	Intron 7 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8537

AN:

151394

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.0538

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.0990

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0511

Gnomad FIN

AF:

0.0954

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0576

GnomAD2 exomes

AF:

0.0516

AC:

10330

AN:

200180

AF XY:

0.0521

show subpopulations

Gnomad AFR exome

AF:

0.0857

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0964

Gnomad EAS exome

AF:

0.0157

Gnomad FIN exome

AF:

0.100

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0538

GnomAD4 exome

AF:

0.0438

AC:

55415

AN:

1265092

Hom.:

1526

Cov.:

AF XY:

0.0446

AC XY:

28342

AN XY:

635012

show subpopulations

African (AFR)

AF:

0.0905

AC:

2668

AN:

29494

American (AMR)

AF:

0.0253

AC:

1009

AN:

39818

Ashkenazi Jewish (ASJ)

AF:

0.0999

AC:

2450

AN:

24526

East Asian (EAS)

AF:

0.00837

AC:

308

AN:

36816

South Asian (SAS)

AF:

0.0530

AC:

4221

AN:

79694

European-Finnish (FIN)

AF:

0.0926

AC:

4763

AN:

51428

Middle Eastern (MID)

AF:

0.0867

AC:

471

AN:

5432

European-Non Finnish (NFE)

AF:

0.0391

AC:

36892

AN:

944142

Other (OTH)

AF:

0.0490

AC:

2633

AN:

53742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

2721

5441

8162

10882

13603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1298

2596

3894

5192

6490

<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:

0.0564

AC:

8552

AN:

151512

Hom.:

314

Cov.:

AF XY:

0.0587

AC XY:

4345

AN XY:

73972

show subpopulations

African (AFR)

AF:

0.0808

AC:

3336

AN:

41264

American (AMR)

AF:

0.0303

AC:

461

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.0990

AC:

343

AN:

3466

East Asian (EAS)

AF:

0.0148

AC:

AN:

5130

South Asian (SAS)

AF:

0.0509

AC:

244

AN:

4790

European-Finnish (FIN)

AF:

0.0954

AC:

998

AN:

10456

Middle Eastern (MID)

AF:

0.120

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0426

AC:

2890

AN:

67878

Other (OTH)

AF:

0.0570

AC:

120

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

372

743

1115

1486

1858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0478

Hom.:

440

Bravo

AF:

0.0530

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 18, 2013

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.4

(source)

DANN

Benign

0.70

PhyloP100

-0.021

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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