NM_004655.4:c.169C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004655.4(AXIN2):​c.169C>T​(p.Arg57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R57Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

AXIN2
NM_004655.4 missense

Scores

4
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.09

Publications

0 publications found
Variant links:
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]
AXIN2 Gene-Disease associations (from GenCC):
  • oligodontia-cancer predisposition syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • tooth agenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • craniosynostosis
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.169C>T p.Arg57Trp missense_variant Exon 2 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.169C>T p.Arg57Trp missense_variant Exon 2 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
ENSG00000266076ENST00000577662.1 linkn.*345C>T non_coding_transcript_exon_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3
ENSG00000266076ENST00000577662.1 linkn.*345C>T 3_prime_UTR_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1
Aug 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 57 of the AXIN2 protein (p.Arg57Trp). This variant is not present in population databases (gnomAD no frequency). 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: 464565). 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 expected to disrupt AXIN2 protein function with a positive 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 10, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R57W variant (also known as c.169C>T), located in coding exon 1 of the AXIN2 gene, results from a C to T substitution at nucleotide position 169. The arginine at codon 57 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Benign
0.96
DEOGEN2
Uncertain
0.48
.;.;T;T;T;.;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Pathogenic
0.98
.;D;D;.;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.67
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.38
D
PhyloP100
2.1
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.1
D;.;.;D;.;.;.;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0010
D;.;.;D;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;.;.;.;.
Polyphen
1.0
.;.;D;D;.;.;.;.
Vest4
0.78
MutPred
0.17
Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);Loss of phosphorylation at T55 (P = 0.0536);
MVP
0.58
MPC
0.73
ClinPred
1.0
D
GERP RS
3.7
PromoterAI
-0.077
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.65
Mutation Taster
=36/64
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555583686; hg19: chr17-63554570; API