chr1-20648577-C-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
Consequence
NM_032409.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PINK1 | ENST00000321556.5 | c.1196C>T | p.Pro399Leu | missense_variant | Exon 6 of 8 | 1 | NM_032409.3 | ENSP00000364204.3 | ||
PINK1 | ENST00000400490.2 | n.289C>T | non_coding_transcript_exon_variant | Exon 2 of 4 | 2 | |||||
PINK1-AS | ENST00000451424.1 | n.3617G>A | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 | |||||
PINK1 | ENST00000492302.1 | n.2284C>T | non_coding_transcript_exon_variant | Exon 4 of 5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251240Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135854
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727228
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74498
ClinVar
Submissions by phenotype
Parkinson disease, autosomal recessive early-onset, digenic, PINK1/DJ1 Pathogenic:1
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Autosomal recessive early-onset Parkinson disease 6 Uncertain:1
The PINK1 c.1196C>T (p.Pro399Leu) missense variant has been reported in one study in which it is found in a heterozygous state in two siblings with early-onset Parkinson disease, both of whom also carried a missense variant in the PARK7 gene (Tang et al. 2006). The variant was additionally found in a heterozygous state in their unaffected mother; their father was not tested. Although early-onset Parkinson disease typically manifests before 40 years of age, a 42-year-old unaffected family member was also shown to carry both variants suggesting incomplete penetrance. The p.Pro399Leu variant was absent from 568 control chromosomes but is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The Pro399 residue is highly conserved. Functional studies by multiple groups and in multiple cell types suggest that the p.Pro399Leu variant impairs protein stability and antioxidative neuroprotective function, Parkin ubiquitination, degradation, and recruitment to mitochondria (Tang et al. 2006; Xiong et al. 2009; Narendra et al. 2013). Based on the evidence, the p.Pro399Leu variant is classified as a variant of unknown significance, but suspicious for pathogenicity of Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at