17-65530019-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004655.4(AXIN2):c.2489T>C(p.Met830Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,890 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 (★★).
Frequency
Consequence
NM_004655.4 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 |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2489T>C | p.Met830Thr | missense_variant | Exon 11 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.2294T>C | p.Met765Thr | missense_variant | Exon 9 of 9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.2294T>C | p.Met765Thr | missense_variant | Exon 10 of 10 | 5 | ENSP00000478916.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 830 of the AXIN2 protein (p.Met830Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 572057). 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 (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15735151) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.M830T variant (also known as c.2489T>C), located in coding exon 10 of the AXIN2 gene, results from a T to C substitution at nucleotide position 2489. The methionine at codon 830 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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