rs1064794189

Variant names:

• chr17-65537827-CTCT-C
• rs1064794189
• NM_004655.4:c.1206_1208delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_004655.4(AXIN2):​c.1206_1208delAGA​(p.Glu403del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E402E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN2 NM_004655.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.98
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004655.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1206_1208delAGA	p.Glu403del	disruptive_inframe_deletion	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.1206_1208delAGA	p.Glu403del	disruptive_inframe_deletion	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1206_1208delAGA	p.Glu403del	disruptive_inframe_deletion	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1206_1208delAGA	p.Glu403del	disruptive_inframe_deletion	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Apr 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 419927). 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 variant, c.1206_1208del, results in the deletion of 1 amino acid(s) of the AXIN2 protein (p.Glu403del), but otherwise preserves the integrity of the reading frame. -

not provided Uncertain:1

Oct 27, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This in-frame deletion of 3 nucleotides in AXIN2 is denoted c.1206_1208delAGA at the cDNA level and p.Glu403del (E403del) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATGA[AGA]GAGA. This deletion of a single Glutamic Acid residue occurs at a position that is not conserved across species and is located in the GSK3-beta binding domain (Hughes 2007). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider AXIN2 Glu403del to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1206_1208delAGA variant (also known as p.E403del) is located in coding exon 5 of the AXIN2 gene. This variant results from an in-frame AGA deletion at nucleotide positions 1206 to 1208. This results in the in-frame deletion of a glutamic acid at codon 403. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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
PhyloP100		7.0

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

Other links and lift over

dbSNP: rs1064794189; hg19: chr17-63533945;