NM_032409.3:c.1196C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032409.3(PINK1):​c.1196C>T​(p.Pro399Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

8
7
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.06
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PINK1NM_032409.3 linkc.1196C>T p.Pro399Leu missense_variant Exon 6 of 8 ENST00000321556.5 NP_115785.1 Q9BXM7-1
PINK1-ASNR_046507.1 linkn.3617G>A 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.1196C>T p.Pro399Leu missense_variant Exon 6 of 8 1 NM_032409.3 ENSP00000364204.3 Q9BXM7-1
PINK1ENST00000400490.2 linkn.289C>T non_coding_transcript_exon_variant Exon 2 of 4 2
PINK1-ASENST00000451424.1 linkn.3617G>A non_coding_transcript_exon_variant Exon 1 of 3 2
PINK1ENST00000492302.1 linkn.2284C>T non_coding_transcript_exon_variant Exon 4 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251240
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461856
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Parkinson disease, autosomal recessive early-onset, digenic, PINK1/DJ1 Pathogenic:1
Jun 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.33
T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D
M_CAP
Uncertain
0.087
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Benign
2.0
M
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-9.0
D
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.81
Gain of catalytic residue at P399 (P = 0.0093);
MVP
0.95
MPC
0.71
ClinPred
0.90
D
GERP RS
6.2
Varity_R
0.80
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs119451946; hg19: chr1-20975070; API