rs138302371
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_032409.3(PINK1):c.587C>T(p.Pro196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P196S) has been classified as Likely benign.
Frequency
Consequence
NM_032409.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PINK1 | NM_032409.3 | c.587C>T | p.Pro196Leu | missense_variant | 2/8 | ENST00000321556.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PINK1 | ENST00000321556.5 | c.587C>T | p.Pro196Leu | missense_variant | 2/8 | 1 | NM_032409.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000187 AC: 47AN: 251350Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135886
GnomAD4 exome AF: 0.000287 AC: 419AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 205AN XY: 727248
GnomAD4 genome AF: 0.000164 AC: 25AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Reported in patients with Parkinson disease in published literature; however, additional clinical information and segregation information were not provided (Marongiu et al., 2008; Song et al., 2013); Reported previously as a variant of uncertain significance in two patients with a diagnosis of ALS and a family history of dementia; however, one patient also harbored a variant in a different gene and no segregation information was provided (Vacchiano et al., 2022); Reported previously in a patient with a clinical diagnosis of ALS who also was an unaffected carrier of a homoplasmic mitochondrial variant (Amore et al., 2023); Published functional studies demonstrate a damaging effect showing that P196L was unable to promote mitochondrial localization of Parkin (Song et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23857047, 32853481, 22644621, 16009891, 16547921, 18330912, 34426522, Ma2022[thesis], 35893043, 36066624, 23303188) - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Autosomal recessive early-onset Parkinson disease 6 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 196 of the PINK1 protein (p.Pro196Leu). This variant is present in population databases (rs138302371, gnomAD 0.03%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 16009891, 23303188). ClinVar contains an entry for this variant (Variation ID: 445908). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PINK1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PINK1 function (PMID: 23303188). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at