rs1204515719

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000540.3(RYR1):c.-65G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.019 ( 0 hom., cov: 0)

Exomes 𝑓: 0.12 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RYR1
NM_000540.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 0.515

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.-65G>C		5_prime_UTR	Exon 1 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.-65G>C		5_prime_UTR	Exon 1 of 105	NP_001036188.1	P21817-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.-65G>C	5_prime_UTR	Exon 1 of 106	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8	TSL:1	c.-65G>C	5_prime_UTR	Exon 1 of 105	ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.6	TSL:1	n.-65G>C	non_coding_transcript_exon	Exon 1 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

217

AN:

11190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.0179

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.0283

Gnomad SAS

AF:

0.0479

Gnomad FIN

AF:

0.0370

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0127

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.124

AC:

21518

AN:

174076

Hom.:

Cov.:

AF XY:

0.115

AC XY:

11405

AN XY:

98908

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.139

AC:

574

AN:

4124

American (AMR)

AF:

0.0568

AC:

709

AN:

12474

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

866

AN:

6426

East Asian (EAS)

AF:

0.190

AC:

1789

AN:

9436

South Asian (SAS)

AF:

0.0388

AC:

802

AN:

20682

European-Finnish (FIN)

AF:

0.0759

AC:

1243

AN:

16372

Middle Eastern (MID)

AF:

0.176

AC:

105

AN:

598

European-Non Finnish (NFE)

AF:

0.146

AC:

13984

AN:

95684

Other (OTH)

AF:

0.175

AC:

1446

AN:

8280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.284

Heterozygous variant carriers

1730

3459

5189

6918

8648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

160

240

320

400

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0192

AC:

215

AN:

11222

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

104

AN XY:

5908

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0143

AC:

AN:

2376

American (AMR)

AF:

0.0172

AC:

AN:

1224

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

280

East Asian (EAS)

AF:

0.0286

AC:

AN:

664

South Asian (SAS)

AF:

0.0477

AC:

AN:

440

European-Finnish (FIN)

AF:

0.0370

AC:

AN:

648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0165

AC:

AN:

5348

Other (OTH)

AF:

0.0122

AC:

AN:

164

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

101

135

169

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:

0.0139

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Central core myopathy (1)

Congenital multicore myopathy with external ophthalmoplegia (1)

Malignant hyperthermia, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.0

(source)

DANN

Benign

0.48

PhyloP100

0.52

PromoterAI

-0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over