rs774657791
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004655.4(AXIN2):c.1209G>T(p.Glu403Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,405,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1209G>T | p.Glu403Asp | missense_variant | Exon 6 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1209G>T | p.Glu403Asp | missense_variant | Exon 5 of 9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1209G>T | p.Glu403Asp | missense_variant | Exon 6 of 10 | 5 | ENSP00000478916.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000111 AC: 2AN: 179450Hom.: 0 AF XY: 0.0000103 AC XY: 1AN XY: 97180
GnomAD4 exome AF: 0.0000142 AC: 20AN: 1405198Hom.: 0 Cov.: 36 AF XY: 0.0000130 AC XY: 9AN XY: 692752
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 403 of the AXIN2 protein (p.Glu403Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 408778). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AXIN2 protein function with a negative predictive value of 80%. 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 Uncertain:1
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in at least one individual with colorectal cancer (Raskin et al., 2017); This variant is associated with the following publications: (PMID: 15735151, 29212164) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.E403D variant (also known as c.1209G>T), located in coding exon 5 of the AXIN2 gene, results from a G to T substitution at nucleotide position 1209. The glutamic acid at codon 403 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was reported in 1/1046 familial CRC cases and was not observed in 1006 healthy controls.(Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is highly 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at