rs756551019
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004655.4(AXIN2):c.1582A>G(p.Lys528Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,658 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 -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1582A>G | p.Lys528Glu | missense_variant | Exon 6 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1582A>G | p.Lys528Glu | missense_variant | Exon 5 of 9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1582A>G | p.Lys528Glu | missense_variant | Exon 6 of 10 | 5 | ENSP00000478916.1 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151782Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251446Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461876Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151782Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74098
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); 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 -
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not specified Uncertain:1
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Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 528 of the AXIN2 protein (p.Lys528Glu). This variant is present in population databases (rs756551019, 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: 464557). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Colorectal cancer Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.K528E variant (also known as c.1582A>G), located in coding exon 5 of the AXIN2 gene, results from an A to G substitution at nucleotide position 1582. The lysine at codon 528 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is 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