17-65558094-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004655.4(AXIN2):​c.527C>A​(p.Thr176Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

AXIN2
NM_004655.4 missense

Scores

8
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.55
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3969097).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.527C>A p.Thr176Asn 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.527C>A p.Thr176Asn missense_variant Exon 2 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
ENSG00000266076ENST00000577662.1 linkn.*703C>A non_coding_transcript_exon_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3
ENSG00000266076ENST00000577662.1 linkn.*703C>A 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: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1
May 02, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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: 1520507). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 176 of the AXIN2 protein (p.Thr176Asn). -

Hereditary cancer-predisposing syndrome Benign:1
Mar 07, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
24
DANN
Benign
0.92
DEOGEN2
Benign
0.28
.;T;T;T;.;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.97
.;D;.;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.40
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.1
D;.;D;.;.;.
REVEL
Benign
0.21
Sift
Uncertain
0.011
D;.;D;.;.;.
Sift4G
Uncertain
0.015
D;D;D;.;.;.
Polyphen
0.98
.;D;D;.;.;.
Vest4
0.72
MutPred
0.41
Gain of disorder (P = 0.1426);Gain of disorder (P = 0.1426);Gain of disorder (P = 0.1426);Gain of disorder (P = 0.1426);Gain of disorder (P = 0.1426);Gain of disorder (P = 0.1426);
MVP
0.50
MPC
0.70
ClinPred
0.95
D
GERP RS
4.6
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-63554212; API