17-65537814-C-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004655.4(AXIN2):c.1222G>A(p.Glu408Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000153 in 1,572,552 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
AXIN2
NM_004655.4 missense
NM_004655.4 missense
Scores
1
3
14
Clinical Significance
Conservation
PhyloP100: 3.62
Genes affected
AXIN2 (HGNC:904): (axin 2) The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.10790479).
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1222G>A | p.Glu408Lys | missense_variant | 6/11 | ENST00000307078.10 | NP_004646.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1222G>A | p.Glu408Lys | missense_variant | 6/11 | 1 | NM_004655.4 | ENSP00000302625 | P1 | |
AXIN2 | ENST00000375702.5 | c.1222G>A | p.Glu408Lys | missense_variant | 5/9 | 1 | ENSP00000364854 | |||
AXIN2 | ENST00000618960.4 | c.1222G>A | p.Glu408Lys | missense_variant | 6/10 | 5 | ENSP00000478916 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000671 AC: 13AN: 193720Hom.: 0 AF XY: 0.0000474 AC XY: 5AN XY: 105408
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GnomAD4 exome AF: 0.0000127 AC: 18AN: 1420528Hom.: 0 Cov.: 36 AF XY: 0.0000142 AC XY: 10AN XY: 702456
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74238
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 27, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the AXIN2 protein (p.Glu408Lys). This variant is present in population databases (rs749846538, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medulloblastoma (PMID: 17373666). ClinVar contains an entry for this variant (Variation ID: 408784). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2022 | The p.E408K variant (also known as c.1222G>A), located in coding exon 5 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 25, 2022 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with medulloblastoma and absent in unaffected controls (PMID: 17373666); This variant is associated with the following publications: (PMID: 15735151, 17373666) - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 09, 2023 | - - |
Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 02, 2024 | - - |
AXIN2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 14, 2024 | The AXIN2 c.1222G>A variant is predicted to result in the amino acid substitution p.Glu408Lys. This variant has been reported in an individual with medulloblastoma (Koch et al. 2007. PubMed ID: 17373666). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/408784/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Benign
T;.;T
Sift4G
Benign
T;T;T
Polyphen
0.38
.;B;B
Vest4
MutPred
Gain of ubiquitination at E408 (P = 9e-04);Gain of ubiquitination at E408 (P = 9e-04);Gain of ubiquitination at E408 (P = 9e-04);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at