rs376628384

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000540.3(RYR1):c.11259+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,602,202 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.629

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), 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-38532772-G-A is Benign according to our data. Variant chr19-38532772-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256400.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00196 (299/152296) while in subpopulation AMR AF = 0.00451 (69/15298). AF 95% confidence interval is 0.00366. There are 1 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.11259+36G>A		intron_variant	Intron 78 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.11259+36G>A		intron_variant	Intron 78 of 105	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

299

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00154

AC:

384

AN:

249088

AF XY:

0.00157

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00211

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00231

AC:

3348

AN:

1449906

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1661

AN XY:

721826

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

33254

American (AMR)

AF:

0.00132

AC:

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.000314

AC:

AN:

85870

European-Finnish (FIN)

AF:

0.00181

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.00151

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

0.00273

AC:

3014

AN:

1102184

Other (OTH)

AF:

0.00227

AC:

136

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

189

378

567

756

945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

220

330

440

550

<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:

0.00196

AC:

299

AN:

152296

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41568

American (AMR)

AF:

0.00451

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00260

AC:

177

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00230

Hom.:

Bravo

AF:

0.00187

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.85

CADD

Benign

3.0

(source)

DANN

Benign

0.69

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism

(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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over