rs755990979

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004655.4(AXIN2):​c.370G>T​(p.Asp124Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AXIN2
NM_004655.4 missense

Scores

9
4
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AXIN2NM_004655.4 linkuse as main transcriptc.370G>T p.Asp124Tyr missense_variant 2/11 ENST00000307078.10 NP_004646.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkuse as main transcriptc.370G>T p.Asp124Tyr missense_variant 2/111 NM_004655.4 ENSP00000302625 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 24, 2022This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 124 of the AXIN2 protein (p.Asp124Tyr). This variant is not present in population databases (gnomAD no frequency). 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: 963102). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
29
DANN
Benign
0.94
DEOGEN2
Benign
0.32
.;.;T;T;T;.;.;.
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
.;D;D;.;D;D;D;D
M_CAP
Benign
0.054
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.77
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-6.3
D;.;.;D;.;.;.;D
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D;.;.;D;.;.;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D;.;.;.;.
Polyphen
1.0
.;.;D;D;.;.;.;.
Vest4
0.84
MutPred
0.42
Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);Gain of MoRF binding (P = 0.0325);
MVP
0.41
MPC
0.80
ClinPred
0.99
D
GERP RS
4.6
gMVP
0.82

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