17-65537769-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004655.4(AXIN2):c.1267C>G(p.Leu423Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,586,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. L423F) has been classified as Likely benign.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1267C>G | p.Leu423Val | missense_variant | 6/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1267C>G | p.Leu423Val | missense_variant | 6/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1267C>G | p.Leu423Val | missense_variant | 5/9 | 1 | |||
AXIN2 | ENST00000618960.4 | c.1267C>G | p.Leu423Val | missense_variant | 6/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000499 AC: 1AN: 200590Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 108596
GnomAD4 exome AF: 0.00000488 AC: 7AN: 1434190Hom.: 0 Cov.: 37 AF XY: 0.00000563 AC XY: 4AN XY: 710600
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152056Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74248
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 01, 2023 | 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. 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 expected to disrupt AXIN2 protein function. ClinVar contains an entry for this variant (Variation ID: 1764423). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. This variant is present in population databases (rs376630432, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 423 of the AXIN2 protein (p.Leu423Val). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2021 | The p.L423V variant (also known as c.1267C>G), located in coding exon 5 of the AXIN2 gene, results from a C to G substitution at nucleotide position 1267. The leucine at codon 423 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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