9-21971134-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_058195.4(CDKN2A):āc.268C>Gā(p.Arg90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,596,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_058195.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000579755.2 | c.268C>G | p.Arg90Gly | missense_variant | Exon 2 of 3 | 1 | NM_058195.4 | ENSP00000462950.1 | ||
CDKN2A | ENST00000304494.10 | c.225C>G | p.Pro75Pro | synonymous_variant | Exon 2 of 3 | 1 | NM_000077.5 | ENSP00000307101.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000927 AC: 2AN: 215646Hom.: 0 AF XY: 0.00000836 AC XY: 1AN XY: 119676
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1444056Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3AN XY: 718446
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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The p.R90G variant (also known as c.268C>G), located in coding exon 2 of the CDKN2A (p14ARF) gene, results from a C to G substitution at nucleotide position 268. The arginine at codon 90 is replaced by glycine, an amino acid with dissimilar properties. This alteration was detected in a cohort of 308 childhood acute lymphoblastic leukemia cases (Li C et al. Pharmacogenet Genomics, 2022 Feb;32:43-50). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Familial melanoma Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 90 of the CDKN2A (p14ARF) protein (p.Arg90Gly). This variant is present in population databases (rs762397298, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 230923). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at