chr17-65558251-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_004655.4(AXIN2):c.370G>A(p.Asp124Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,894 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 Conflicting classifications of pathogenicity (no stars).
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.370G>A | p.Asp124Asn | missense_variant | Exon 2 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
ENSG00000266076 | ENST00000577662.1 | n.*546G>A | non_coding_transcript_exon_variant | Exon 4 of 7 | 2 | ENSP00000462418.1 | ||||
ENSG00000266076 | ENST00000577662.1 | n.*546G>A | 3_prime_UTR_variant | Exon 4 of 7 | 2 | ENSP00000462418.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
AXIN2: BP1 -
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; This variant is associated with the following publications: (PMID: 15735151) -
The AXIN2 c.370G>A (p.Asp124Asn) variant has not been reported in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/251494 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 124 of the AXIN2 protein (p.Asp124Asn). This variant is present in population databases (rs755990979, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of AXIN2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 408772). 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. -
not specified Uncertain:1
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Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
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Colorectal cancer Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at