rs137854598
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PM2PM5PP3_StrongBS2_Supporting
The NM_000077.5(CDKN2A):c.305C>T(p.Ala102Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,452,980 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A102E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.305C>T | p.Ala102Val | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.348C>T | p.Gly116= | synonymous_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.305C>T | p.Ala102Val | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.348C>T | p.Gly116= | synonymous_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1452980Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5AN XY: 723124
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9053859, 16354195, 16234564, 31026031, 26681309, 25064638, 37611275) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | The p.A102V variant (also known as c.305C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 305. The alanine at codon 102 is replaced by valine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with melanoma (Potrony M et al. J. Am. Acad. Dermatol., 2014 Nov;71:888-95). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 | Jul 02, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 234071). This variant is also known as c.348C>T (Silent) in the CDKN2A (p14ARF) transcript. This missense change has been observed in individual(s) with melanoma (PMID: 26681309). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 102 of the CDKN2A (p16INK4a) protein (p.Ala102Val). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at