rs371061924

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.13188G>A​(p.Pro4396Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,503,080 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 (★★).

Frequency

Genomes: 𝑓 0.000046 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

RYR1
NM_000540.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.425

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

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=-0.61).
BP6
Variant 19-38565522-G-A is Benign according to our data. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38565522-G-A is described in CliVar as Likely_benign. Clinvar id is 256425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.425 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.13188G>A p.Pro4396Pro synonymous_variant Exon 91 of 106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.13188G>A p.Pro4396Pro synonymous_variant Exon 91 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000396
AC:
4
AN:
100946
AF XY:
0.0000533
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000478
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000318
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000325
GnomAD4 exome
AF:
0.00000814
AC:
11
AN:
1350890
Hom.:
0
Cov.:
31
AF XY:
0.00000901
AC XY:
6
AN XY:
666076
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
27642
American (AMR)
AF:
0.00
AC:
0
AN:
32660
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24078
East Asian (EAS)
AF:
0.0000949
AC:
3
AN:
31596
South Asian (SAS)
AF:
0.00
AC:
0
AN:
75836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33310
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3980
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1065446
Other (OTH)
AF:
0.000142
AC:
8
AN:
56342
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000460
AC:
7
AN:
152190
Hom.:
1
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74420
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41564
American (AMR)
AF:
0.0000654
AC:
1
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10576
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67970
Other (OTH)
AF:
0.00237
AC:
5
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000113
Asia WGS
AF:
0.00580
AC:
20
AN:
3462

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
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

- -

RYR1-related disorder Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.61
CADD
Benign
8.5
DANN
Benign
0.96
PhyloP100
-0.42
PromoterAI
0.019
Neutral

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: rs371061924; hg19: chr19-39056162; API