rs763142730

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032409.3(PINK1):c.199C>T(p.Leu67Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,543,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.638

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056676656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINK1	NM_032409.3 link	c.199C>T	p.Leu67Phe	missense_variant	Exon 1 of 8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
MIR6084	NR_106732.1 link	n.69C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR6084	unassigned_transcript_48	n.-9C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5 link	c.199C>T	p.Leu67Phe	missense_variant	Exon 1 of 8	1	NM_032409.3	ENSP00000364204.3		Q9BXM7-1
MIR6084	ENST00000622012.1 link	n.69C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000499

AC:

AN:

140376

AF XY:

0.0000776

show subpopulations

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:

0.000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

165

AN:

1391262

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

687512

show subpopulations

African (AFR)

AF:

0.0000626

AC:

AN:

31962

American (AMR)

AF:

0.00

AC:

AN:

36278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

36382

South Asian (SAS)

AF:

0.00

AC:

AN:

79752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5044

European-Non Finnish (NFE)

AF:

0.000148

AC:

160

AN:

1082462

Other (OTH)

AF:

0.0000517

AC:

AN:

58026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000380

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 6

Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 67 of the PINK1 protein (p.Leu67Phe). This variant is present in population databases (rs763142730, gnomAD 0.01%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 18330912). ClinVar contains an entry for this variant (Variation ID: 1416013). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PINK1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.064

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

0.64

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.77

REVEL

Benign

0.090

Sift

Benign

0.17

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.082

MutPred

0.26

Loss of catalytic residue at L67 (P = 0.073);

MVP

0.60

MPC

0.19

ClinPred

0.043

GERP RS

-0.60

PromoterAI

0.36

Neutral

(source)

Varity_R

0.051

gMVP

0.24

Mutation Taster

=84/16

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs763142730

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over