rs751229839

Positions:

• chr17-65537796-G-A

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000418 AC: 6 AN: 1434284 Hom.: 0 Cov.: 37 AF XY: 0.00000422 AC XY: 3 AN XY: 710824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000546

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	.;T;.
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.65	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.034	D;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.99	.;D;D
Vest4		0.71
MutPred		0.15		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		0.41
MPC		0.67
ClinPred		0.51	D
GERP RS		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751229839; hg19: chr17-63533914; COSMIC: COSV100195894; COSMIC: COSV100195894;