rs760625400

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004655.4(AXIN2):c.158C>G(p.Ser53Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.72

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 links:

ENSG00000266076 (HGNC:):

ENSG00000266076 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20656651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4 link	c.158C>G	p.Ser53Cys	missense_variant	Exon 2 of 11	ENST00000307078.10	NP_004646.3	Q9Y2T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AXIN2	ENST00000307078.10 link	c.158C>G	p.Ser53Cys	missense_variant	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
ENSG00000266076	ENST00000577662.1 link	n.*334C>G		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000462418.1	J3KSC3
ENSG00000266076	ENST00000577662.1 link	n.*334C>G		3_prime_UTR_variant	Exon 4 of 7	2		ENSP00000462418.1	J3KSC3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245300

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132404

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:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451382

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720526

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Jan 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the AXIN2 protein (p.Ser53Cys). This variant is present in population databases (rs760625400, gnomAD 0.0009%). 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: 1025523). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

Nov 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S53C variant (also known as c.158C>G), located in coding exon 1 of the AXIN2 gene, results from a C to G substitution at nucleotide position 158. The serine at codon 53 is replaced by cysteine, an amino acid with dissimilar properties. In one study, this variant was detected in 1/1231 colorectal cancer cases and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.068

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.77

DEOGEN2

Benign

0.30

.;.;T;T;T;.;.;.

Eigen

Benign

0.089

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

.;T;T;.;T;T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.083

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

N;.;.;N;.;.;.;N

REVEL

Benign

0.21

Sift

Uncertain

0.0040

D;.;.;D;.;.;.;D

Sift4G

Uncertain

0.0050

D;D;D;D;.;.;.;.

Polyphen

0.011

.;.;B;B;.;.;.;.

Vest4

0.17

MVP

0.71

MPC

0.21

ClinPred

0.39

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over