1-20644665-A-T

Position:

chr1-20644665-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032409.3(PINK1):c.952A>T(p.Met318Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,614,172 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 1 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 8.04

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]

PINK1 links:

PINK1 (HGNC:):

PINK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07187414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PINK1	NM_032409.3 linkuse as main transcript	c.952A>T	p.Met318Leu	missense_variant	4/8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
PINK1-AS	NR_046507.1 linkuse as main transcript	n.3981+920T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PINK1	ENST00000321556.5 linkuse as main transcript	c.952A>T	p.Met318Leu	missense_variant	4/8	1	NM_032409.3	ENSP00000364204.3	Q9BXM7-1
PINK1	ENST00000492302.1 linkuse as main transcript	n.2040A>T		non_coding_transcript_exon_variant	2/5	2
PINK1-AS	ENST00000451424.1 linkuse as main transcript	n.3981+920T>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000900

AC:

226

AN:

251094

Hom.:

AF XY:

0.000847

AC XY:

115

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000724

AC:

1058

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000688

AC XY:

500

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.000769

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152340

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00102

AC:

124

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PINK1: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16755580, 22118943, 15970950, 22644621, 18330912, 19351622, 16547921, 22243833, 27094865, 15596610, 21412950, 34426522, 27393345, 24660942, 30665447, 33921279, 35954270) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 04, 2023	BS1 -

Autosomal recessive early-onset Parkinson disease 6

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 318 of the PINK1 protein (p.Met318Leu). This variant is present in population databases (rs139226733, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with in the heterozygous state in several individuals affected with late onset Parkinson's disease (PMID: 15596610, 16755580, 19351622, 22243833, 24660942, 27094865). ClinVar contains an entry for this variant (Variation ID: 447942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PINK1 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 03, 2017

- -

PINK1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The PINK1 c.952A>T variant is predicted to result in the amino acid substitution p.Met318Leu. This variant has been reported in the heterozygous state in multiple individuals with both late- and early-onset Parkinson's disease (Rogaeva et al. 2004. PubMed ID: 15596610; Djarmati et al. 2006. PubMed ID: 16755580; Brooks et al. 2009. PubMed ID: 19351622; Pihlstrøm et al. 2014. PubMed ID: 24660942; Bandrés-Ciga et al. 2016. PubMed ID: 27393345; Kuzkina et al. 2022. PubMed ID: 37248217). In vitro functional studies have shown that this variant leads to a loss of PINK1 phosphorylation activity (Broadway et al. 2022. PubMed ID: 35954270). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

M_CAP

Benign

0.039

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

0.089

Vest4

0.77

MutPred

0.88

Gain of methylation at K319 (P = 0.0356);

MVP

0.88

MPC

0.20

ClinPred

0.077

GERP RS

6.1

Varity_R

0.67

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over