rs751229839
Positions:
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
NM_004655.4 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 2.37
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]
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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 |
---|---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1240C>T | p.Arg414Trp | missense_variant | 6/11 | ENST00000307078.10 | NP_004646.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1240C>T | p.Arg414Trp | missense_variant | 6/11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1240C>T | p.Arg414Trp | missense_variant | 5/9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1240C>T | p.Arg414Trp | missense_variant | 6/10 | 5 | ENSP00000478916.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000418 AC: 6AN: 1434284Hom.: 0 Cov.: 37 AF XY: 0.00000422 AC XY: 3AN XY: 710824
GnomAD4 exome
AF:
AC:
6
AN:
1434284
Hom.:
Cov.:
37
AF XY:
AC XY:
3
AN XY:
710824
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ExAC
AF:
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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 09, 2023 | 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. 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 submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2022 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Benign
D;.;T
Sift4G
Benign
T;T;T
Polyphen
0.99
.;D;D
Vest4
MutPred
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
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at