rs115477764

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032409.3(PINK1):c.1426G>A(p.Glu476Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,210 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.248

Publications

19 publications found

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=0.004126638).

BP6

Variant 1-20649169-G-A is Benign according to our data. Variant chr1-20649169-G-A is described in ClinVar as Benign. ClinVar VariationId is 286390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1706/152354) while in subpopulation AFR AF = 0.0385 (1600/41584). AF 95% confidence interval is 0.0369. There are 31 homozygotes in GnomAd4. There are 834 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINK1	NM_032409.3 link	c.1426G>A	p.Glu476Lys	missense_variant	Exon 7 of 8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
PINK1-AS	NR_046507.1 link	n.3025C>T		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.1426G>A	p.Glu476Lys	missense_variant	Exon 7 of 8	1	NM_032409.3	ENSP00000364204.3	Q9BXM7-1
PINK1	ENST00000400490.2 link	n.519G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
PINK1-AS	ENST00000451424.1 link	n.3025C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
PINK1	ENST00000492302.1 link	n.2876G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1706

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00313

AC:

785

AN:

251042

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00113

AC:

1646

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000972

AC XY:

707

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0372

AC:

1247

AN:

33478

American (AMR)

AF:

0.00277

AC:

124

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

1112006

Other (OTH)

AF:

0.00305

AC:

184

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

218

328

437

546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0112

AC:

1706

AN:

152354

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

834

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0385

AC:

1600

AN:

41584

American (AMR)

AF:

0.00516

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68040

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00404

Hom.:

Bravo

AF:

0.0133

ESP6500AA

AF:

0.0429

AC:

189

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00401

AC:

487

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 19, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26274610, 27884173, 15349860, 20981092, 22644621, 20558144) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PINK1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive early-onset Parkinson disease 6

Benign:3

Aug 05, 2021

Fulgent Genetics, Fulgent Genetics

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

- -

Oct 19, 2017

Illumina Laboratory Services, Illumina

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Feb 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PINK1-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.25

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.8

REVEL

Benign

0.13

Sift

Benign

0.43

Sift4G

Benign

0.61

Polyphen

0.036

Vest4

0.19

MVP

0.68

MPC

0.20

ClinPred

0.0019

GERP RS

2.1

Varity_R

0.050

gMVP

0.37

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over