rs587782792
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000077.5(CDKN2A):c.251A>T(p.Asp84Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D84N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.251A>T | p.Asp84Val | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.294A>T | p.Arg98= | synonymous_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.251A>T | p.Asp84Val | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.294A>T | p.Arg98= | synonymous_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial melanoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 26775776, 28060055). It has also been observed to segregate with disease in related individuals. 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10491434, 21462282). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.