19-38502722-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_000540.3(RYR1):c.7830C>T(p.Leu2610Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,416,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2610L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.655

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-38502722-C-T is Benign according to our data. Variant chr19-38502722-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.655 with no splicing effect.

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.7830C>T	p.Leu2610Leu	synonymous	Exon 48 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.7830C>T	p.Leu2610Leu	synonymous	Exon 48 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7830C>T	p.Leu2610Leu	synonymous	Exon 48 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.7830C>T	p.Leu2610Leu	synonymous	Exon 48 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.7830C>T		non_coding_transcript_exon	Exon 48 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.000482

AC:

AN:

132690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000413

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000268

Gnomad FIN

AF:

0.000134

Gnomad MID

AF:

0.00385

Gnomad NFE

AF:

0.000801

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000644

AC:

155

AN:

240582

AF XY:

0.000710

show subpopulations

Gnomad AFR exome

AF:

0.000317

Gnomad AMR exome

AF:

0.000498

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000720

Gnomad FIN exome

AF:

0.000122

Gnomad NFE exome

AF:

0.000988

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000802

AC:

1030

AN:

1284086

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

524

AN XY:

637894

show subpopulations

African (AFR)

AF:

0.000370

AC:

AN:

29750

American (AMR)

AF:

0.000417

AC:

AN:

40722

Ashkenazi Jewish (ASJ)

AF:

0.0000506

AC:

AN:

19744

East Asian (EAS)

AF:

0.000680

AC:

AN:

26472

South Asian (SAS)

AF:

0.000463

AC:

AN:

84192

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

33750

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.000905

AC:

900

AN:

994968

Other (OTH)

AF:

0.000685

AC:

AN:

49622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000482

AC:

AN:

132810

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

AN XY:

63212

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

36712

American (AMR)

AF:

0.000412

AC:

AN:

12136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3256

East Asian (EAS)

AF:

0.00

AC:

AN:

4170

South Asian (SAS)

AF:

0.000268

AC:

AN:

3738

European-Finnish (FIN)

AF:

0.000134

AC:

AN:

7438

Middle Eastern (MID)

AF:

0.00420

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000801

AC:

AN:

62436

Other (OTH)

AF:

0.00

AC:

AN:

1840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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:

0.000618

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Malignant hyperthermia, susceptibility to, 1 (1)

RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

3.4

(source)

DANN

Benign

0.86

PhyloP100

-0.66

Mutation Taster

=99/1

polymorphism

(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

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