rs104894104
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000077.5(CDKN2A):c.340C>T(p.Pro114Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.
Frequency
Consequence
NM_000077.5 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 |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.340C>T | p.Pro114Ser | missense_variant | Exon 2 of 3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755.2 | c.383C>T | p.Ala128Val | missense_variant | Exon 2 of 3 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1455220Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 724210
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74500
ClinVar
Submissions by phenotype
Familial melanoma Uncertain:1
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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of p.Pro114Ser variant on p16INK4a protein function (PMID: 9053859, 19260062, 21462282, 23190892, 24659262). The functional impact of p.Ala128Val on p14ARF has not been tested. This missense change has been observed in individual(s) with melanoma (PMID: 11579459, 21462282, 16905682, 17492760, 19484507, 17992122, 17047042, 26775776, 22841127). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 114 of the p16INK4a protein (p.Pro114Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. Alternatively, this sequence change replaces alanine with valine at codon 128 of the p14ARF protein (p.Ala128Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at