chr17-65537772-G-A

Position:

• chr17-65537772-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004655.4(AXIN2):​c.1264C>T​(p.Pro422Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,434,404 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (1 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.43

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15405285).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1264C>T	p.Pro422Ser	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.1264C>T	p.Pro422Ser	missense_variant	6/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.1264C>T	p.Pro422Ser	missense_variant	5/9	1		ENSP00000364854
AXIN2	ENST00000618960.4	c.1264C>T	p.Pro422Ser	missense_variant	6/10	5		ENSP00000478916

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000999 AC: 2 AN: 200134 Hom.: 1 AF XY: 0.00 AC XY: 0 AN XY: 108450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000234

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1434404 Hom.: 1 Cov.: 37 AF XY: 0.00000422 AC XY: 3 AN XY: 710744

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000546

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000601 Hom.: 1

Bravo AF: 0.00000378

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

Nov 27, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 422 of the AXIN2 protein (p.Pro422Ser). 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 variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 239979). 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 not expected to disrupt AXIN2 protein function with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2022

The p.P422S variant (also known as c.1264C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1264. The proline at codon 422 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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	0.078
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.29	.;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;T;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.64	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.89	N;.;N
REVEL	Benign	0.25
Sift	Benign	0.20	T;.;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.016	.;B;B
Vest4		0.25
MutPred		0.10		Gain of phosphorylation at P422 (P = 0.0213);Gain of phosphorylation at P422 (P = 0.0213);Gain of phosphorylation at P422 (P = 0.0213);
MVP		0.49
MPC		0.19
ClinPred		0.074	T
GERP RS		1.7
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854718; hg19: chr17-63533890;