rs1043424

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

1
17

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

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 rank MANE Protein UniProt
PINK1NM_032409.3 linkc.1562A>C p.Asn521Thr missense_variant Exon 8 of 8 ENST00000321556.5 NP_115785.1 Q9BXM7-1
PINK1-ASNR_046507.1 linkn.1687T>G non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PINK1ENST00000321556.5 linkc.1562A>C p.Asn521Thr missense_variant Exon 8 of 8 1 NM_032409.3 ENSP00000364204.3 Q9BXM7-1
PINK1ENST00000400490.2 linkn.655A>C non_coding_transcript_exon_variant Exon 4 of 4 2
PINK1-ASENST00000451424.1 linkn.1687T>G non_coding_transcript_exon_variant Exon 1 of 3 2
PINK1ENST00000492302.1 linkn.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.:
33
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.:
57
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.:
33
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
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
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

- -

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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 07, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive early-onset Parkinson disease 6 Benign:4
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. -

Sep 05, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.60
T
MetaRNN
Benign
0.0024
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.94
N
REVEL
Benign
0.040
Sift
Benign
0.25
T
Sift4G
Benign
0.41
T
Polyphen
0.022
B
Vest4
0.10
MPC
0.18
ClinPred
0.0024
T
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.

Other links and lift over

dbSNP: rs1043424; hg19: chr1-20977000; COSMIC: COSV58630745; COSMIC: COSV58630745; API