ClinVar

Description

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that p.Thr93Arg in p16INK4a is likely to be disruptive. These same algorithms do not agree on the potential impact of p.His107Gln in p14ARF (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDKN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 232366). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 93 of the CDKN2A (p16INK4a) protein (p.Thr93Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. Alternatively, this sequence change replaces histidine with glutamine at codon 107 of the CDKN2A (p14ARF) protein (p.His107Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine.