19-38442480-G-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.270+27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,568,804 control chromosomes in the GnomAD database, including 17,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1483 hom., cov: 31)

Exomes 𝑓: 0.14 ( 15791 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.365

Publications

6 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=-0.88).

BP6

Variant 19-38442480-G-A is Benign according to our data. Variant chr19-38442480-G-A is described in ClinVar as Benign. ClinVar VariationId is 133119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 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.270+27G>A		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.270+27G>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.270+27G>A	intron	N/A	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.270+27G>A	intron	N/A	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.270+27G>A	intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19598

AN:

151820

Hom.:

1487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.100

GnomAD2 exomes

AF:

0.156

AC:

38856

AN:

249018

AF XY:

0.157

show subpopulations

Gnomad AFR exome

AF:

0.0995

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.317

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.143

AC:

202682

AN:

1416866

Hom.:

15791

Cov.:

AF XY:

0.144

AC XY:

102231

AN XY:

707484

show subpopulations

African (AFR)

AF:

0.0938

AC:

3061

AN:

32642

American (AMR)

AF:

0.170

AC:

7593

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

3318

AN:

25808

East Asian (EAS)

AF:

0.295

AC:

11661

AN:

39506

South Asian (SAS)

AF:

0.210

AC:

17969

AN:

85390

European-Finnish (FIN)

AF:

0.123

AC:

6544

AN:

53320

Middle Eastern (MID)

AF:

0.0830

AC:

442

AN:

5326

European-Non Finnish (NFE)

AF:

0.134

AC:

144029

AN:

1071442

Other (OTH)

AF:

0.137

AC:

8065

AN:

58866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

8808

17616

26424

35232

44040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5456

10912

16368

21824

27280

<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:

0.129

AC:

19595

AN:

151938

Hom.:

1483

Cov.:

AF XY:

0.133

AC XY:

9870

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.101

AC:

4170

AN:

41468

American (AMR)

AF:

0.144

AC:

2205

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

404

AN:

3468

East Asian (EAS)

AF:

0.305

AC:

1561

AN:

5112

South Asian (SAS)

AF:

0.227

AC:

1092

AN:

4804

European-Finnish (FIN)

AF:

0.121

AC:

1282

AN:

10584

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8601

AN:

67920

Other (OTH)

AF:

0.104

AC:

220

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

841

1683

2524

3366

4207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.122

Hom.:

1859

Bravo

AF:

0.128

Asia WGS

AF:

0.303

AC:

1053

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.3

(source)

DANN

Benign

0.94

PhyloP100

0.36

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