17-65537751-C-G

Variant names:

• chr17-65537751-C-G
• rs773119996
• NM_004655.4:c.1285G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004655.4(AXIN2):​c.1285G>C​(p.Gly429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G429S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 publications found

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]

AXIN2 Gene-Disease associations (from GenCC):

• oligodontia-cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1285G>C	p.Gly429Arg	missense_variant	Exon 6 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1285G>C	p.Gly429Arg	missense_variant	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1285G>C	p.Gly429Arg	missense_variant	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1285G>C	p.Gly429Arg	missense_variant	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424288 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 704994

African (AFR) AF: 0.00 AC: 0 AN: 32698

American (AMR) AF: 0.00 AC: 0 AN: 38748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 37726

South Asian (SAS) AF: 0.00 AC: 0 AN: 81716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092742

Other (OTH) AF: 0.00 AC: 0 AN: 58990

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G429R variant (also known as c.1285G>C), located in coding exon 5 of the AXIN2 gene, results from a G to C substitution at nucleotide position 1285. The glycine at codon 429 is replaced by arginine, an amino acid with dissimilar 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	0.25
BayesDel_addAF	Benign	0.0000066	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		3.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.81	.;P;P
Vest4		0.42
MutPred		0.084		Loss of glycosylation at S428 (P = 0.0537);Loss of glycosylation at S428 (P = 0.0537);Loss of glycosylation at S428 (P = 0.0537);
MVP		0.64
MPC		0.68
ClinPred		0.77	D
GERP RS		2.9
gMVP		0.36
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773119996; hg19: chr17-63533869;