17-65537489-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_004655.4(AXIN2):āc.1547A>Cā(p.His516Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
AXIN2
NM_004655.4 missense
NM_004655.4 missense
Scores
5
10
3
Clinical Significance
Conservation
PhyloP100: 7.52
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, 0.784
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1547A>C | p.His516Pro | missense_variant | 6/11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1547A>C | p.His516Pro | missense_variant | 5/9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1547A>C | p.His516Pro | missense_variant | 6/10 | 5 | ENSP00000478916.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251390Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461864Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727238
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GnomAD4 genome Cov.: 31
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31
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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2019 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with AXIN2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with proline at codon 516 of the AXIN2 protein (p.His516Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Uncertain
T;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at