rs138302371

chr1-20638041-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032409.3(PINK1):c.587C>T(p.Pro196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P196S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3 linkuse as main transcript	c.587C>T	p.Pro196Leu	missense_variant	2/8	ENST00000321556.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5 linkuse as main transcript	c.587C>T	p.Pro196Leu	missense_variant	2/8	1	NM_032409.3	P1	Q9BXM7-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251350

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000287

AC:

419

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

205

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000164

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	Reported in patients with Parkinson disease in published literature; however, additional clinical information and segregation information were not provided (Marongiu et al., 2008; Song et al., 2013); Reported previously as a variant of uncertain significance in two patients with a diagnosis of ALS and a family history of dementia; however, one patient also harbored a variant in a different gene and no segregation information was provided (Vacchiano et al., 2022); Reported previously in a patient with a clinical diagnosis of ALS who also was an unaffected carrier of a homoplasmic mitochondrial variant (Amore et al., 2023); Published functional studies demonstrate a damaging effect showing that P196L was unable to promote mitochondrial localization of Parkin (Song et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23857047, 32853481, 22644621, 16009891, 16547921, 18330912, 34426522, Ma2022[thesis], 35893043, 36066624, 23303188) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive early-onset Parkinson disease 6

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 196 of the PINK1 protein (p.Pro196Leu). This variant is present in population databases (rs138302371, gnomAD 0.03%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 16009891, 23303188). ClinVar contains an entry for this variant (Variation ID: 445908). 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 not expected to disrupt PINK1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PINK1 function (PMID: 23303188). 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

0.070

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.10

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.58

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.95

REVEL

Uncertain

0.38

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0060

Polyphen

0.38

Vest4

0.70

MVP

0.83

MPC

0.27

ClinPred

0.054

GERP RS

5.0

Varity_R

0.041

gMVP

0.41

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