1-20633636-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_032409.3(PINK1):c.88G>C(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,318,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.390

Publications

5 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:

MIR6084 (HGNC:50235): (microRNA 6084) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6084 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008400917).

BP6

Variant 1-20633636-G-C is Benign according to our data. Variant chr1-20633636-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294997.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00284 (430/151188) while in subpopulation AFR AF = 0.0099 (410/41418). AF 95% confidence interval is 0.00911. There are 0 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.88G>C	p.Gly30Arg	missense	Exon 1 of 8	NP_115785.1	Q9BXM7-1
	MIR6084	NR_106732.1		n.-43G>C		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PINK1	ENST00000321556.5	TSL:1 MANE Select	c.88G>C	p.Gly30Arg	missense	Exon 1 of 8	ENSP00000364204.3	Q9BXM7-1
PINK1	ENST00000878749.1		c.88G>C	p.Gly30Arg	missense	Exon 1 of 8	ENSP00000548808.1
PINK1	ENST00000878743.1		c.88G>C	p.Gly30Arg	missense	Exon 1 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

428

AN:

151082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00988

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000724

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00386

GnomAD2 exomes

AF:

0.00

AC:

AN:

1076

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000333

AC:

389

AN:

1167628

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

169

AN XY:

563504

show subpopulations

African (AFR)

AF:

0.0133

AC:

305

AN:

22866

American (AMR)

AF:

0.000473

AC:

AN:

8450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15364

East Asian (EAS)

AF:

0.00

AC:

AN:

26100

South Asian (SAS)

AF:

0.0000958

AC:

AN:

41740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27016

Middle Eastern (MID)

AF:

0.000310

AC:

AN:

3222

European-Non Finnish (NFE)

AF:

0.0000328

AC:

AN:

975324

Other (OTH)

AF:

0.000904

AC:

AN:

47546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00284

AC:

430

AN:

151188

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

202

AN XY:

73876

show subpopulations

African (AFR)

AF:

0.00990

AC:

410

AN:

41418

American (AMR)

AF:

0.000723

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67544

Other (OTH)

AF:

0.00382

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000697

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive early-onset Parkinson disease 6 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0084

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

PhyloP100

0.39

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.65

REVEL

Benign

0.16

Sift

Uncertain

0.015

Sift4G

Uncertain

0.018

Polyphen

0.81

Vest4

0.17

MVP

0.83

MPC

0.42

ClinPred

0.58

GERP RS

2.5

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over