rs3738136

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032409.3(PINK1):c.1018G>A(p.Ala340Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0641 in 1,613,752 control chromosomes in the GnomAD database, including 5,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 462 hom., cov: 31)

Exomes 𝑓: 0.065 ( 5413 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.03

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-AS (HGNC:38872): (PINK1 antisense RNA)

PINK1-AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056702495).

BP6

Variant 1-20645618-G-A is Benign according to our data. Variant chr1-20645618-G-A is described in ClinVar as [Benign]. Clinvar id is 295004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20645618-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINK1	NM_032409.3 link	c.1018G>A	p.Ala340Thr	missense_variant	Exon 5 of 8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
PINK1-AS	NR_046507.1 link	n.3948C>T		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PINK1	ENST00000321556.5 link	c.1018G>A	p.Ala340Thr	missense_variant	Exon 5 of 8	1	NM_032409.3	ENSP00000364204.3	Q9BXM7-1
PINK1	ENST00000400490.2 link	n.111G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2
PINK1-AS	ENST00000451424.1 link	n.3948C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
PINK1	ENST00000492302.1 link	n.2106G>A		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8320

AN:

151828

Hom.:

461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0627

Gnomad ASJ

AF:

0.0424

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.0869

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0448

Gnomad OTH

AF:

0.0479

GnomAD3 exomes

AF:

0.0921

AC:

23161

AN:

251368

Hom.:

1876

AF XY:

0.0971

AC XY:

13192

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0362

Gnomad EAS exome

AF:

0.265

Gnomad SAS exome

AF:

0.216

Gnomad FIN exome

AF:

0.0930

Gnomad NFE exome

AF:

0.0451

Gnomad OTH exome

AF:

0.0701

GnomAD4 exome

AF:

0.0651

AC:

95106

AN:

1461814

Hom.:

5413

Cov.:

AF XY:

0.0696

AC XY:

50621

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0947

Gnomad4 ASJ exome

AF:

0.0413

Gnomad4 EAS exome

AF:

0.258

Gnomad4 SAS exome

AF:

0.215

Gnomad4 FIN exome

AF:

0.0929

Gnomad4 NFE exome

AF:

0.0460

Gnomad4 OTH exome

AF:

0.0710

GnomAD4 genome

AF:

0.0547

AC:

8316

AN:

151938

Hom.:

462

Cov.:

AF XY:

0.0600

AC XY:

4459

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0163

Gnomad4 AMR

AF:

0.0629

Gnomad4 ASJ

AF:

0.0424

Gnomad4 EAS

AF:

0.260

Gnomad4 SAS

AF:

0.229

Gnomad4 FIN

AF:

0.0869

Gnomad4 NFE

AF:

0.0448

Gnomad4 OTH

AF:

0.0474

Alfa

AF:

0.0484

Hom.:

689

Bravo

AF:

0.0496

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0446

AC:

172

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.0473

AC:

407

ExAC

AF:

0.0921

AC:

11176

Asia WGS

AF:

0.203

AC:

703

AN:

3478

EpiCase

AF:

0.0425

EpiControl

AF:

0.0451

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 24. Only high quality variants are reported. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive early-onset Parkinson disease 6

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23459931, 17084972, 31182772) -

PINK1-related disorder

Benign:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.7

DANN

Benign

0.76

DEOGEN2

Benign

0.069

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.42

PrimateAI

Benign

0.36

PROVEAN

Benign

1.3

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.054

MPC

0.17

ClinPred

0.0016

GERP RS

2.4

Varity_R

0.015

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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