rs1043424

Positions:

Variant summary

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

The NM_032409.3(PINK1):c.1562A>C(p.Asn521Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,613,924 control chromosomes in the GnomAD database, including 66,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 5989 hom., cov: 33)

Exomes 𝑓: 0.29 ( 60999 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.617

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=0.0024134517).

BP6

Variant 1-20650507-A-C is Benign according to our data. Variant chr1-20650507-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 295006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20650507-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PINK1	NM_032409.3 linkuse as main transcript	c.1562A>C	p.Asn521Thr	missense_variant	8/8	ENST00000321556.5	NP_115785.1
PINK1-AS	NR_046507.1 linkuse as main transcript	n.1687T>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5 linkuse as main transcript	c.1562A>C	p.Asn521Thr	missense_variant	8/8	1	NM_032409.3	ENSP00000364204	P1	Q9BXM7-1
PINK1-AS	ENST00000451424.1 linkuse as main transcript	n.1687T>G		non_coding_transcript_exon_variant	1/3	2
PINK1	ENST00000400490.2 linkuse as main transcript	n.655A>C		non_coding_transcript_exon_variant	4/4	2
PINK1	ENST00000492302.1 linkuse as main transcript	n.3012A>C		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42053

AN:

151968

Hom.:

5986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.235

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.383

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.268

GnomAD3 exomes

AF:

0.292

AC:

73476

AN:

251378

Hom.:

11210

AF XY:

0.298

AC XY:

40462

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.192

Gnomad EAS exome

AF:

0.352

Gnomad SAS exome

AF:

0.374

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.278

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.286

AC:

417477

AN:

1461838

Hom.:

60999

Cov.:

AF XY:

0.288

AC XY:

209526

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.199

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.376

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.278

Gnomad4 OTH exome

AF:

0.286

GnomAD4 genome

AF:

0.277

AC:

42073

AN:

152086

Hom.:

5989

Cov.:

AF XY:

0.280

AC XY:

20830

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.234

Gnomad4 ASJ

AF:

0.197

Gnomad4 EAS

AF:

0.347

Gnomad4 SAS

AF:

0.382

Gnomad4 FIN

AF:

0.352

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.265

Alfa

AF:

0.270

Hom.:

14863

Bravo

AF:

0.268

TwinsUK

AF:

0.271

AC:

1005

ALSPAC

AF:

0.284

AC:

1094

ESP6500AA

AF:

0.268

AC:

1179

ESP6500EA

AF:

0.271

AC:

2333

ExAC

AF:

0.297

AC:

36089

Asia WGS

AF:

0.314

AC:

1092

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 49% 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: 46. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -

Autosomal recessive early-onset Parkinson disease 6

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 31182772, 30917570, 21677397, 23303188, 23459931) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital disorder of glycosylation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Parkinson Disease, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.94

REVEL

Benign

0.040

Sift

Benign

0.25

Sift4G

Benign

0.41

Polyphen

0.022

Vest4

0.10

MPC

0.18

ClinPred

0.0024

GERP RS

1.6

Varity_R

0.061

gMVP

0.090

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