17-65536530-T-G

Position:

• chr17-65536530-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004655.4(AXIN2):​c.1931A>C​(p.Tyr644Ser) 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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10164356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1931A>C	p.Tyr644Ser	missense_variant	8/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1931A>C	p.Tyr644Ser	missense_variant	8/11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1736A>C	p.Tyr579Ser	missense_variant	6/9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1736A>C	p.Tyr579Ser	missense_variant	7/10	5		ENSP00000478916.1
AXIN2	ENST00000578251.1	n.153A>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

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

Dec 08, 2024

The p.Y644S variant (also known as c.1931A>C), located in coding exon 7 of the AXIN2 gene, results from an A to C substitution at nucleotide position 1931. The tyrosine at codon 644 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.22	.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.63	.;T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.80	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.39	T;.;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0030	.;B;B
Vest4		0.37
MutPred		0.15		Loss of stability (P = 0.0861);.;.;
MVP		0.20
MPC		0.25
ClinPred		0.034	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs1025003994; hg19: chr17-63532648; COSMIC: COSV61055754; COSMIC: COSV61055754;