9-21974734-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000077.5(CDKN2A):c.94C>G(p.Leu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,394 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_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.94C>G | p.Leu32Val | missense_variant | Exon 1 of 3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755.2 | c.194-3526C>G | intron_variant | Intron 1 of 2 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000821 AC: 2AN: 243524Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133218
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460394Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726538
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Melanoma and neural system tumor syndrome Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.L32V variant (also known as c.94C>G), located in coding exon 1 of the CDKN2A gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Familial melanoma Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 32 of the CDKN2A (p16INK4a) protein (p.Leu32Val). This variant is present in population databases (rs745827714, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 532278). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Leu32 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8595405, 16905682, 17047042, 19712690, 20340136, 28592523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at