rs1060502147

Positions:

• chr17-65535704-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000307078.10(AXIN2):​c.2159A>G​(p.Gln720Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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. Q720E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 ENST00000307078.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.76

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2540667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.2159A>G	p.Gln720Arg	missense_variant	9/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.2159A>G	p.Gln720Arg	missense_variant	9/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.1964A>G	p.Gln655Arg	missense_variant	7/9	1		ENSP00000364854
AXIN2	ENST00000618960.4	c.1964A>G	p.Gln655Arg	missense_variant	8/10	5		ENSP00000478916
AXIN2	ENST00000578251.1	n.381A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 09, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 408824). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 720 of the AXIN2 protein (p.Gln720Arg). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2023

The p.Q720R variant (also known as c.2159A>G), located in coding exon 8 of the AXIN2 gene, results from an A to G substitution at nucleotide position 2159. The glutamine at codon 720 is replaced by arginine, an amino acid with highly similar 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	0.087
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	.;T;.
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.59	N;.;N
REVEL	Benign	0.11
Sift	Benign	0.56	T;.;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.97	.;D;D
Vest4		0.46
MutPred		0.21		Gain of MoRF binding (P = 0.0165);.;.;
MVP		0.53
MPC		0.55
ClinPred		0.50	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30

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: rs1060502147; hg19: chr17-63531822;