rs2240307

Positions:

• chr17-65558189-A-C
• chr17-65558189-A-G
• chr17-65558189-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004655.4(AXIN2):​c.432T>G​(p.Ile144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I144V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3570009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.432T>G	p.Ile144Met	missense_variant	2/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.432T>G	p.Ile144Met	missense_variant	2/11	1	NM_004655.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.75
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0019	P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;.;N;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D;.;D;.;.;.;.
Sift4G	Uncertain	0.010	D;D;D;.;.;.;.
Polyphen		0.78	.;P;P;.;.;.;.
Vest4		0.46
MutPred		0.40		Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);Loss of catalytic residue at L149 (P = 0.0567);
MVP		0.27
MPC		0.55
ClinPred		0.92	D
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.36

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: chr17-63554307;