chr9-21974815-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting
The NM_000077.5(CDKN2A):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,448,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. A5E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.13G>A | p.Ala5Thr | missense_variant | 1/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.194-3607G>A | intron_variant | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.13G>A | p.Ala5Thr | missense_variant | 1/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.194-3607G>A | intron_variant | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000414 AC: 6AN: 1448480Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2AN XY: 720644
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2024 | The p.A5T variant (also known as c.13G>A), located in coding exon 1 of the CDKN2A gene, results from a G to A substitution at nucleotide position 13. The alanine at codon 5 is replaced by threonine, an amino acid with similar properties. This variant has been identified in individuals diagnosed with melanoma (Soufir N et al. Br. J. Cancer 2004 Jan; 90(2):503-9; Puig S et al. Genet. Med. 2016 Jul;18(7):727-36; Taylor NJ et al. J Invest Dermatol, 2017 12;137:2606-2612). This amino acid position is conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 25, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of melanoma (Soufir et al., 2004; Miller et al., 2011; Puig et al., 2016); This variant is associated with the following publications: (PMID: 21085193, 25064638, 14735200, 21462282, 28830827, 26681309) - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the CDKN2A (p16INK4a) protein (p.Ala5Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 14735200, 26681309, 28830827). ClinVar contains an entry for this variant (Variation ID: 233536). 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 tolerated. 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