9-21974706-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting
The NM_000077.5(CDKN2A):c.122C>A(p.Pro41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P41P) has been classified as Benign.
Frequency
Consequence
NM_000077.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000304494.10 | c.122C>A | p.Pro41Gln | missense_variant | Exon 1 of 3 | 1 | NM_000077.5 | ENSP00000307101.5 | ||
CDKN2A | ENST00000579755.2 | c.194-3498C>A | intron_variant | Intron 1 of 2 | 1 | NM_058195.4 | ENSP00000462950.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000327 AC: 8AN: 244752Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133500
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460848Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726730
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152042Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74284
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces proline with glutamine at codon 41 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study has reported this variant was neutral in a cell proliferation assay (PMID: 35001868). This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has been identified in 9/276116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Ovarian cancer Pathogenic:1
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not specified Uncertain:1
Variant summary: CDKN2A c.122C>A (p.Pro41Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 244752 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.122C>A has been reported in the literature in individuals affected with pancreatic ductal adenocarcinoma, also in control subjects (Xu_2015, Yin_2022, Okawa_2023). These report(s) 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 protein function. These results showed no damaging effect of this variant by an in vitro cell proliferation assay (Kimura_2022). The following publications have been ascertained in the context of this evaluation (PMID: 27756164, 27960642, 28765326, 9166859, 35001868, 16818274, 18519632, 36243179, 7718873, 26104880, 35171259). ClinVar contains an entry for this variant (Variation ID: 141111). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Melanoma and neural system tumor syndrome Uncertain:1
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not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate neutral cell proliferation effects (Kimura et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 35001868) -
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
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 41 of the CDKN2A (p16INK4a) protein (p.Pro41Gln). This variant is present in population databases (rs373407950, gnomAD 0.05%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma and acute lymphoblastic leukemia (PMID: 26104880, 35171259). ClinVar contains an entry for this variant (Variation ID: 141111). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 35001868). 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