17-65558251-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_004655.4(AXIN2):​c.370G>A​(p.Asp124Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

1
7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 7.79
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41464388).
BP6
Variant 17-65558251-C-T is Benign according to our data. Variant chr17-65558251-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408772.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.370G>A p.Asp124Asn 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.370G>A p.Asp124Asn missense_variant Exon 2 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
ENSG00000266076ENST00000577662.1 linkn.*546G>A non_coding_transcript_exon_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3
ENSG00000266076ENST00000577662.1 linkn.*546G>A 3_prime_UTR_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251494
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 29, 2024The AXIN2 c.370G>A (p.Asp124Asn) variant has not been reported in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/251494 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 10, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15735151) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024AXIN2: BP1 -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 11, 2023This 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Aug 12, 2021- -
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2025This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 124 of the AXIN2 protein (p.Asp124Asn). This variant is present in population databases (rs755990979, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of AXIN2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 408772). 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025- -
Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 21, 2024- -
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsAug 31, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
25
DANN
Benign
0.97
DEOGEN2
Benign
0.27
.;.;T;T;T;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.99
.;D;D;.;D;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.41
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.86
T
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.5
D;.;.;D;.;.;.;D
REVEL
Benign
0.26
Sift
Uncertain
0.0020
D;.;.;D;.;.;.;D
Sift4G
Uncertain
0.0030
D;D;D;D;.;.;.;.
Polyphen
1.0
.;.;D;D;.;.;.;.
Vest4
0.69
MVP
0.38
MPC
0.68
ClinPred
0.94
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

LitVar

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

Other links and lift over

dbSNP: rs755990979; hg19: chr17-63554369; API