rs140344858

chr17-65530080-C-Achr17-65530080-C-Gchr17-65530080-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_004655.4(AXIN2):c.2428G>T(p.Asp810Tyr) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D810H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-65530080-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1422755.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.2428G>T	p.Asp810Tyr	missense_variant	11/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.2428G>T	p.Asp810Tyr	missense_variant	11/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.2233G>T	p.Asp745Tyr	missense_variant	9/9	1
AXIN2	ENST00000618960.4	c.2233G>T	p.Asp745Tyr	missense_variant	10/10	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 810 of the AXIN2 protein (p.Asp810Tyr). 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: 857256). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AXIN2 protein function. 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	Benign	0.29
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.3	D;.;D
REVEL	Uncertain	0.34
Sift	Benign	0.036	D;.;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.71
MutPred		0.63		Gain of MoRF binding (P = 0.0599);.;.;
MVP		0.47
MPC		0.79
ClinPred		0.99	D
GERP RS		3.6
gMVP		0.61

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

Other links and lift over

dbSNP: rs140344858; hg19: chr17-63526198;