1-20633613-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_032409.3(PINK1):​c.65C>T​(p.Thr22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000883 in 1,132,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

Publications

0 publications found
Variant links:
Genes affected
PINK1 (HGNC:14581): (PTEN induced kinase 1) This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]
MIR6084 (HGNC:50235): (microRNA 6084) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35913503).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PINK1NM_032409.3 linkc.65C>T p.Thr22Met missense_variant Exon 1 of 8 ENST00000321556.5 NP_115785.1 Q9BXM7-1
MIR6084NR_106732.1 linkn.-66C>T upstream_gene_variant
MIR6084unassigned_transcript_48 n.-143C>T upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PINK1ENST00000321556.5 linkc.65C>T p.Thr22Met missense_variant Exon 1 of 8 1 NM_032409.3 ENSP00000364204.3 Q9BXM7-1
MIR6084ENST00000622012.1 linkn.-66C>T upstream_gene_variant 6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
8.83e-7
AC:
1
AN:
1132268
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
542104
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
22434
American (AMR)
AF:
0.00
AC:
0
AN:
7960
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14580
East Asian (EAS)
AF:
0.00
AC:
0
AN:
25124
South Asian (SAS)
AF:
0.00
AC:
0
AN:
34184
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
25064
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3064
European-Non Finnish (NFE)
AF:
0.00000105
AC:
1
AN:
954004
Other (OTH)
AF:
0.00
AC:
0
AN:
45854
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 6 Uncertain:1
Jan 17, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 22 of the PINK1 protein (p.Thr22Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PINK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.061
T
Eigen
Benign
0.16
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.57
T
M_CAP
Pathogenic
0.54
D
MetaRNN
Benign
0.36
T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
1.9
M
PhyloP100
1.7
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
0.59
N
REVEL
Benign
0.18
Sift
Benign
0.14
T
Sift4G
Benign
0.22
T
Polyphen
0.98
D
Vest4
0.24
MutPred
0.22
Loss of phosphorylation at T22 (P = 0.0334);
MVP
0.88
MPC
0.53
ClinPred
0.78
D
GERP RS
3.6
PromoterAI
-0.016
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.051
gMVP
0.31
Mutation Taster
=91/9
polymorphism

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

hg19: chr1-20960106; API