17-65536872-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004655.4(AXIN2):c.1904A>G(p.His635Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. H635L) has been classified 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1904A>G | p.His635Arg | missense_variant | 7/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1904A>G | p.His635Arg | missense_variant | 7/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1713-319A>G | intron_variant | 1 | |||||
AXIN2 | ENST00000618960.4 | c.1713-319A>G | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250792Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135668
GnomAD4 exome AF: 0.0000240 AC: 35AN: 1460858Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 726732
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2020 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 08, 2023 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000062 (8/128558 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 635 of the AXIN2 protein (p.His635Arg). This variant is present in population databases (rs775207779, gnomAD 0.006%). 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: 234541). 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;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 09, 2022 | - - |
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2022 | The p.H635R variant (also known as c.1904A>G), located in coding exon 6 of the AXIN2 gene, results from an A to G substitution at nucleotide position 1904. The histidine at codon 635 is replaced by arginine, an amino acid with highly similar 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