rs587780123
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004655.4(AXIN2):c.2123C>T(p.Ser708Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,612,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S708W) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.2123C>T | p.Ser708Leu | missense_variant | 8/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2123C>T | p.Ser708Leu | missense_variant | 8/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1928C>T | p.Ser643Leu | missense_variant | 6/9 | 1 | |||
AXIN2 | ENST00000618960.4 | c.1928C>T | p.Ser643Leu | missense_variant | 7/10 | 5 | |||
AXIN2 | ENST00000578251.1 | n.345C>T | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000167 AC: 4AN: 239944Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130476
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1459906Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15AN XY: 726156
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74346
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 708 of the AXIN2 protein (p.Ser708Leu). This variant is present in population databases (rs587780123, 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: 127942). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AXIN2 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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 | Nov 01, 2023 | The p.S708L variant (also known as c.2123C>T), located in coding exon 7 of the AXIN2 gene, results from a C to T substitution at nucleotide position 2123. The serine at codon 708 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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