rs1554656344
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000077.5(CDKN2A):c.101C>T(p.Ala34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A34T) has been classified 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.101C>T | p.Ala34Val | missense_variant | 1/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.194-3519C>T | intron_variant | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.101C>T | p.Ala34Val | missense_variant | 1/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.194-3519C>T | intron_variant | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460594Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726652
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2023 | The p.A34V variant (also known as c.101C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 101. The alanine at codon 34 is replaced by valine, an amino acid with similar properties. This variant has been identified individually and in conjunction with a pathogenic CDKN2A mutation in an Austrian melanoma cohort (Burgstaller-Muehlbacher S et al. Melanoma Res., 2015 Oct;25:412-20; Müller C et al. Br. J. Dermatol., 2016 Jun;174:1308-17). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the CDKN2A (p16INK4a) protein (p.Ala34Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 26225579, 26800492). ClinVar contains an entry for this variant (Variation ID: 483329). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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