17-65537822-T-C

Variant summary

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

The NM_004655.4(AXIN2):c.1214A>G(p.Glu405Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E405A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1214A>G	p.Glu405Gly	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1214A>G	p.Glu405Gly	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1214A>G	p.Glu405Gly	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1214A>G	p.Glu405Gly	missense_variant	6/10	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408220 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 694610

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2023

The p.E405G variant (also known as c.1214A>G), located in coding exon 5 of the AXIN2 gene, results from an A to G substitution at nucleotide position 1214. The glutamic acid at codon 405 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.12
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.030
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.2	D;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;.;T
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.32	.;B;B
Vest4		0.53
MutPred		0.12		Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);
MVP		0.51
MPC		0.26
ClinPred		0.95	D
GERP RS		4.9
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-63533940;