1-20650507-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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 was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PINK1	NM_032409.3 link	c.1562A>C	p.Asn521Thr	missense_variant	Exon 8 of 8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
PINK1-AS	NR_046507.1 link	n.1687T>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PINK1	ENST00000321556.5 link	c.1562A>C	p.Asn521Thr	missense_variant	Exon 8 of 8	1	NM_032409.3	ENSP00000364204.3	Q9BXM7-1
PINK1	ENST00000400490.2 link	n.655A>C		non_coding_transcript_exon_variant	Exon 4 of 4	2
PINK1-AS	ENST00000451424.1 link	n.1687T>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
PINK1	ENST00000492302.1 link	n.3012A>C		non_coding_transcript_exon_variant	Exon 5 of 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

GnomAD2 exomes

AF:

0.292

AC:

73476

AN:

251378

AF XY:

0.298

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 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

AC:

8632

AN:

33474

Gnomad4 AMR exome

AF:

0.229

AC:

10261

AN:

44716

Gnomad4 ASJ exome

AF:

0.199

AC:

5193

AN:

26136

Gnomad4 EAS exome

AF:

0.334

AC:

13263

AN:

39698

Gnomad4 SAS exome

AF:

0.376

AC:

32423

AN:

86254

Gnomad4 FIN exome

AF:

0.365

AC:

19505

AN:

53414

Gnomad4 NFE exome

AF:

0.278

AC:

309674

AN:

1111988

Gnomad4 Remaining exome

AF:

0.286

AC:

17267

AN:

60390

Heterozygous variant carriers

19719

39438

59157

78876

98595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

10404

20808

31212

41616

52020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.261319

AN:

0.261319

Gnomad4 AMR

AF:

0.234

AC:

0.234332

AN:

0.234332

Gnomad4 ASJ

AF:

0.197

AC:

0.196717

AN:

0.196717

Gnomad4 EAS

AF:

0.347

AC:

0.34705

AN:

0.34705

Gnomad4 SAS

AF:

0.382

AC:

0.381645

AN:

0.381645

Gnomad4 FIN

AF:

0.352

AC:

0.352118

AN:

0.352118

Gnomad4 NFE

AF:

0.275

AC:

0.275379

AN:

0.275379

Gnomad4 OTH

AF:

0.265

AC:

0.265152

AN:

0.265152

Heterozygous variant carriers

1595

3191

4786

6382

7977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.271

Hom.:

23292

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 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. -

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:Likely 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: 31182772, 30917570, 21677397, 23303188, 23459931) -

Congenital disorder of glycosylation

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkinson Disease, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

Mutation Taster

=96/4

polymorphism (auto)

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