rs751229839

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004655.4(AXIN2):​c.1240C>T​(p.Arg414Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,434,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

1
6
11

Clinical Significance

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

Conservation

PhyloP100: 2.37
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AXIN2NM_004655.4 linkuse as main transcriptc.1240C>T p.Arg414Trp missense_variant 6/11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkuse as main transcriptc.1240C>T p.Arg414Trp missense_variant 6/111 NM_004655.4 ENSP00000302625.5 Q9Y2T1
AXIN2ENST00000375702.5 linkuse as main transcriptc.1240C>T p.Arg414Trp missense_variant 5/91 ENSP00000364854.5 E7ES00
AXIN2ENST00000618960.4 linkuse as main transcriptc.1240C>T p.Arg414Trp missense_variant 6/105 ENSP00000478916.1 E7ES00

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000418
AC:
6
AN:
1434284
Hom.:
0
Cov.:
37
AF XY:
0.00000422
AC XY:
3
AN XY:
710824
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:
0.00000546
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000826
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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 09, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 533146). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 414 of the AXIN2 protein (p.Arg414Trp). -
Colorectal cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 28, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 05, 2022The p.R414W variant (also known as c.1240C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1240. The arginine at codon 414 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. 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
0.092
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
.;T;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.35
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.78
.;T;.
M_CAP
Pathogenic
0.72
D
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Benign
-0.65
T
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.4
N;.;N
REVEL
Uncertain
0.31
Sift
Benign
0.034
D;.;T
Sift4G
Benign
0.19
T;T;T
Polyphen
0.99
.;D;D
Vest4
0.71
MutPred
0.15
Loss of phosphorylation at S413 (P = 0.0768);Loss of phosphorylation at S413 (P = 0.0768);Loss of phosphorylation at S413 (P = 0.0768);
MVP
0.41
MPC
0.67
ClinPred
0.51
D
GERP RS
0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs751229839; hg19: chr17-63533914; COSMIC: COSV100195894; COSMIC: COSV100195894; API