9-21971161-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000077.5(CDKN2A):c.198C>G(p.His66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,442,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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 -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.198C>G | p.His66Gln | missense_variant | Exon 2 of 3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755.2 | c.241C>G | p.Arg81Gly | missense_variant | Exon 2 of 3 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000467 AC: 1AN: 214172Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 119490
GnomAD4 exome AF: 0.00000624 AC: 9AN: 1442770Hom.: 0 Cov.: 31 AF XY: 0.00000975 AC XY: 7AN XY: 717830
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The p.H66Q variant (also known as c.198C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 198. The histidine at codon 66 is replaced by glutamine, an amino acid with highly similar properties. 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. -
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not specified Uncertain:1
Variant summary: CDKN2A c.198C>G (p.His66Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 214172 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.198C>G has been reported in the literature in cancer cells from OPSCC and Melanoma patients, although the variant was not confirmed to be of a germline origin rather than somatic (Yang_2005, Khandelwal_2020). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on p32 binding in the ARF protein, derived from an alternate transcript in which the variant would result in p.Arg81Gly (Itahana_2008). This showed that this residue occurs in or near a p32 binding domain and that the variant may inhibit p32 binding. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16354195, 18538737, 30967399, 33134534) -
Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Uncertain:1
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Familial melanoma Uncertain:1
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. This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the CDKN2A (p16INK4a) protein (p.His66Gln). This variant is present in population databases (rs374984975, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.241C>G (p.Arg81Gly) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 573530). 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