rs750325162
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The ENST00000366898.6(PRKN):āc.775A>Gā(p.Ile259Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000038 ( 0 hom. )
Consequence
PRKN
ENST00000366898.6 missense
ENST00000366898.6 missense
Scores
11
7
Clinical Significance
Conservation
PhyloP100: 7.08
Genes affected
PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a region_of_interest SYT11 binding 2 (size 36) in uniprot entity PRKN_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000366898.6
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKN | NM_004562.3 | c.775A>G | p.Ile259Val | missense_variant | 7/12 | ENST00000366898.6 | NP_004553.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRKN | ENST00000366898.6 | c.775A>G | p.Ile259Val | missense_variant | 7/12 | 1 | NM_004562.3 | ENSP00000355865 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251278Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
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GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727230
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74312
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the PRKN protein (p.Ile259Val). This variant is present in population databases (rs750325162, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PRKN-related conditions. ClinVar contains an entry for this variant (Variation ID: 581407). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
P;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at