NM_004655.4:c.1387C>A

Variant names:

• chr17-65537649-G-T
• rs730881395
• NM_004655.4:c.1387C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463L) has been classified 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
• 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004655.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1387C>A	p.Arg463Ser	missense	Exon 6 of 11	NP_004646.3
	AXIN2	NM_001363813.1		c.1387C>A	p.Arg463Ser	missense	Exon 6 of 10	NP_001350742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1387C>A	p.Arg463Ser	missense	Exon 6 of 11	ENSP00000302625.5
	AXIN2	ENST00000375702.5	TSL:1	c.1387C>A	p.Arg463Ser	missense	Exon 5 of 9	ENSP00000364854.5
	AXIN2	ENST00000881031.1		c.1387C>A	p.Arg463Ser	missense	Exon 6 of 11	ENSP00000551090.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 37646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25502

East Asian (EAS) AF: 0.00 AC: 0 AN: 38252

South Asian (SAS) AF: 0.00 AC: 0 AN: 83126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45394

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093618

Other (OTH) AF: 0.00 AC: 0 AN: 59112

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.77	T
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Sift4G	Benign	0.61	T
Polyphen		0.70	P
Vest4		0.56
MutPred		0.64		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
Mutation Taster		=22/78	disease causing

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: rs730881395; hg19: chr17-63533767;