rs121913381
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000077.5(CDKN2A):c.322G>T(p.Asp108Tyr) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D108N) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_000077.5 | c.322G>T | p.Asp108Tyr | missense_variant | 2/3 | ENST00000304494.10 | |
CDKN2A | NM_058195.4 | c.365G>T | p.Arg122Leu | missense_variant | 2/3 | ENST00000579755.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.322G>T | p.Asp108Tyr | missense_variant | 2/3 | 1 | NM_000077.5 | P2 | |
CDKN2A | ENST00000579755.2 | c.365G>T | p.Arg122Leu | missense_variant | 2/3 | 1 | NM_058195.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1453704Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723436
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2023 | The p.D108Y variant (also known as c.322G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 322. The aspartic acid at codon 108 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with CDKN2A-related disease (Ambry internal data; Erlandson A et al. J. Invest. Dermatol., 2007 Jun;127:1465-7; Pissa M et al. Acta Oncol, 2021 Jul;60:888-896). Based on internal structural analysis, D108Y is more destabilizing to CDKN2A than internally pathogenic variants at the same position and nearby (Ambry internal data; Byeon IJ et al. Mol Cell 1998 Feb;1(3):421-31; Russo AA et al. Nature 1998 Sep;395(6699):237-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2020 | This variant is not present in population databases (ExAC 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. The p.Asp108Tyr variant has been reported to affect p16INK4a protein function (PMID: 12606942). The functional impact of p.Arg122Leu on p14ARF has not been tested. This variant has been observed in individuals with malignant melanoma (PMID: 17255954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182423). This sequence change replaces aspartic acid with tyrosine at codon 108 of the p16INK4a protein (p.Asp108Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Alternatively, this sequence change replaces arginine with leucine at codon 122 of the p14ARF protein (p.Arg122Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at