17-65537525-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004655.4(AXIN2):​c.1511G>A​(p.Gly504Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. G504R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.78

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21711448).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.1511G>A p.Gly504Asp missense_variant Exon 6 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.1511G>A p.Gly504Asp missense_variant Exon 6 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
AXIN2ENST00000375702.5 linkc.1511G>A p.Gly504Asp missense_variant Exon 5 of 9 1 ENSP00000364854.5 E7ES00
AXIN2ENST00000618960.4 linkc.1511G>A p.Gly504Asp missense_variant Exon 6 of 10 5 ENSP00000478916.1 E7ES00

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
250690
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461698
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000671
AC:
3
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53276
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111978
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1
Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 504 of the AXIN2 protein (p.Gly504Asp). This variant is present in population databases (rs754079144, gnomAD 0.009%). 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: 408843). 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. -

Colorectal cancer Uncertain:1
Oct 12, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Jan 05, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.G504D variant (also known as c.1511G>A), located in coding exon 5 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1511. The glycine at codon 504 is replaced by aspartic acid, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.32
.;T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
0.060
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.81
.;T;.
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.90
T
PhyloP100
2.8
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.50
N;.;N
REVEL
Benign
0.088
Sift
Benign
0.40
T;.;T
Sift4G
Benign
0.55
T;T;T
Polyphen
0.32
.;B;B
Vest4
0.31
MutPred
0.38
Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP
0.55
MPC
0.56
ClinPred
0.32
T
GERP RS
5.1
gMVP
0.36
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs754079144; hg19: chr17-63533643; API