17-65535681-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_004655.4(AXIN2):c.2182G>A(p.Ala728Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign 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. A728G) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2182G>A | p.Ala728Thr | missense_variant | Exon 9 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1987G>A | p.Ala663Thr | missense_variant | Exon 7 of 9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1987G>A | p.Ala663Thr | missense_variant | Exon 8 of 10 | 5 | ENSP00000478916.1 | |||
AXIN2 | ENST00000578251.1 | n.404G>A | non_coding_transcript_exon_variant | Exon 2 of 3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251394Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727244
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74348
ClinVar
Submissions by phenotype
not specified Uncertain:2
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Variant summary: AXIN2 c.2182G>A (p.Ala728Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00025 in 277138 control chromosomes (gnomAD). The observed variant frequency within African control individuals in the gnomAD database is approximately 1.8-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in population(s) of African origin. To our knowledge, no occurrence of c.2182G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
not provided Uncertain:2
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
The AXIN2 c.2182G>A (p.Ala728Thr) variant has not been reported as a germline variant in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.00024 (6/24958 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
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Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 728 of the AXIN2 protein (p.Ala728Thr). This variant is present in population databases (rs141260153, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 464597). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
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Carcinoma of colon;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at