17-65535681-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004655.4(AXIN2):​c.2182G>A​(p.Ala728Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A728G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 0.256
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.043323576).
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.2182G>A p.Ala728Thr missense_variant Exon 9 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.2182G>A p.Ala728Thr missense_variant Exon 9 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
AXIN2ENST00000375702.5 linkc.1987G>A p.Ala663Thr missense_variant Exon 7 of 9 1 ENSP00000364854.5 E7ES00
AXIN2ENST00000618960.4 linkc.1987G>A p.Ala663Thr missense_variant Exon 8 of 10 5 ENSP00000478916.1 E7ES00
AXIN2ENST00000578251.1 linkn.404G>A non_coding_transcript_exon_variant Exon 2 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251394
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000645
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 06, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: AXIN2 c.2182G>A (p.Ala728Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00025 in 277138 control chromosomes (gnomAD). The observed variant frequency within African control individuals in the gnomAD database is approximately 1.8-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in population(s) of African origin. To our knowledge, no occurrence of c.2182G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

not provided Uncertain:2
Mar 11, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

May 01, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The AXIN2 c.2182G>A (p.Ala728Thr) variant has not been reported as a germline variant in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.00024 (6/24958 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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
Feb 24, 2025
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Oct 08, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oligodontia-cancer predisposition syndrome Uncertain:1
Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 728 of the AXIN2 protein (p.Ala728Thr). This variant is present in population databases (rs141260153, gnomAD 0.02%). 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: 464597). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Apr 26, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carcinoma of colon;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
8.5
DANN
Benign
0.70
DEOGEN2
Benign
0.24
.;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.67
.;T;.
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.043
T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.15
N;.;N
REVEL
Benign
0.064
Sift
Benign
0.26
T;.;T
Sift4G
Benign
0.45
T;T;T
Polyphen
0.0010
.;B;B
Vest4
0.12
MVP
0.23
MPC
0.17
ClinPred
0.010
T
GERP RS
0.68
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141260153; hg19: chr17-63531799; API