17-65537649-G-T

Variant names:

• chr17-65537649-G-T
• NM_004655.4:c.1387C>A

Variant summary

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

The NM_004655.4(AXIN2):​c.1387C>A​(p.Arg463Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000704 in 1,421,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • 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: 3.71

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 rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1387C>A	p.Arg463Ser	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.1387C>A	p.Arg463Ser	missense_variant	Exon 6 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1387C>A	p.Arg463Ser	missense_variant	Exon 5 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1387C>A	p.Arg463Ser	missense_variant	Exon 6 of 10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421248 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 703706

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 16, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.77	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.70	.;P;P
Vest4		0.56
MutPred		0.64		Gain of glycosylation at R463 (P = 0.0103);Gain of glycosylation at R463 (P = 0.0103);Gain of glycosylation at R463 (P = 0.0103);
MVP		0.53
MPC		0.46
ClinPred		0.77	D
GERP RS		5.1
gMVP		0.53

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: chr17-63533767;