chr6-161973403-T-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_004562.3(PRKN):c.633A>T(p.Lys211Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,457,332 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K211I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004562.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKN | NM_004562.3 | c.633A>T | p.Lys211Asn | missense_variant | 6/12 | ENST00000366898.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKN | ENST00000366898.6 | c.633A>T | p.Lys211Asn | missense_variant | 6/12 | 1 | NM_004562.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251364Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135858
GnomAD4 exome AF: 0.0000172 AC: 25AN: 1457332Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14AN XY: 725384
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive juvenile Parkinson disease 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | May 09, 2023 | ACMG criteria used to clasify this variant: PM1, PP3_MOD, PS3_SUP, PP2 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2005 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRKN function (PMID: 25591737). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 7051). This missense change has been observed in individual(s) with early-onset Parkinson disease (PMID: 11222808, 15970950, 25833766). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs137853060, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 211 of the PRKN protein (p.Lys211Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at