rs748860876
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000307078.10(AXIN2):c.1747G>A(p.Gly583Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,609,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G583E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000307078.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1747G>A | p.Gly583Arg | missense_variant | 7/11 | ENST00000307078.10 | NP_004646.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1747G>A | p.Gly583Arg | missense_variant | 7/11 | 1 | NM_004655.4 | ENSP00000302625 | P1 | |
AXIN2 | ENST00000375702.5 | c.1712+295G>A | intron_variant | 1 | ENSP00000364854 | |||||
AXIN2 | ENST00000618960.4 | c.1712+295G>A | intron_variant | 5 | ENSP00000478916 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000205 AC: 5AN: 243312Hom.: 0 AF XY: 0.00000754 AC XY: 1AN XY: 132540
GnomAD4 exome AF: 0.0000666 AC: 97AN: 1457366Hom.: 0 Cov.: 34 AF XY: 0.0000634 AC XY: 46AN XY: 725144
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 583 of the AXIN2 protein (p.Gly583Arg). This variant is present in population databases (rs748860876, gnomAD 0.004%). 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: 408773). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 15, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2024 | 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 - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The p.G583R variant (also known as c.1747G>A), located in coding exon 6 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1747. The glycine at codon 583 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at