19-38460307-C-T

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.2361-68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,398,186 control chromosomes in the GnomAD database, including 292,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30108 hom., cov: 31)
Exomes 𝑓: 0.65 ( 262561 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.639

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), 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

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=-0.82).
BP6
Variant 19-38460307-C-T is Benign according to our data. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38460307-C-T is described in CliVar as Benign. Clinvar id is 133115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.2361-68C>T intron_variant Intron 19 of 105 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.2361-68C>T intron_variant Intron 19 of 105 5 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
AF:
0.623
AC:
94673
AN:
151862
Hom.:
30094
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.535
Gnomad AMI
AF:
0.802
Gnomad AMR
AF:
0.689
Gnomad ASJ
AF:
0.670
Gnomad EAS
AF:
0.592
Gnomad SAS
AF:
0.416
Gnomad FIN
AF:
0.709
Gnomad MID
AF:
0.703
Gnomad NFE
AF:
0.661
Gnomad OTH
AF:
0.635
GnomAD4 exome
AF:
0.645
AC:
804070
AN:
1246206
Hom.:
262561
AF XY:
0.638
AC XY:
402028
AN XY:
629914
show subpopulations
African (AFR)
AF:
0.535
AC:
15547
AN:
29084
American (AMR)
AF:
0.688
AC:
30503
AN:
44352
Ashkenazi Jewish (ASJ)
AF:
0.667
AC:
16512
AN:
24762
East Asian (EAS)
AF:
0.648
AC:
25083
AN:
38682
South Asian (SAS)
AF:
0.434
AC:
35386
AN:
81614
European-Finnish (FIN)
AF:
0.694
AC:
36981
AN:
53310
Middle Eastern (MID)
AF:
0.661
AC:
3538
AN:
5352
European-Non Finnish (NFE)
AF:
0.662
AC:
606116
AN:
915768
Other (OTH)
AF:
0.646
AC:
34404
AN:
53282
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
15824
31648
47471
63295
79119
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
14414
28828
43242
57656
72070
<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:
0.623
AC:
94722
AN:
151980
Hom.:
30108
Cov.:
31
AF XY:
0.620
AC XY:
46060
AN XY:
74282
show subpopulations
African (AFR)
AF:
0.535
AC:
22159
AN:
41434
American (AMR)
AF:
0.690
AC:
10534
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.670
AC:
2322
AN:
3466
East Asian (EAS)
AF:
0.593
AC:
3060
AN:
5160
South Asian (SAS)
AF:
0.416
AC:
2003
AN:
4820
European-Finnish (FIN)
AF:
0.709
AC:
7489
AN:
10566
Middle Eastern (MID)
AF:
0.697
AC:
205
AN:
294
European-Non Finnish (NFE)
AF:
0.661
AC:
44889
AN:
67942
Other (OTH)
AF:
0.630
AC:
1330
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
1800
3600
5400
7200
9000
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
766
1532
2298
3064
3830
<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:
0.644
Hom.:
21670
Bravo
AF:
0.624
Asia WGS
AF:
0.452
AC:
1574
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2Other:1
-
RYR1 database
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 14, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.3
DANN
Benign
0.78
PhyloP100
-0.64
Mutation Taster
=22/78
disease causing

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

Other links and lift over

dbSNP: rs2304147; hg19: chr19-38950947; API