17-65537577-G-C

Variant names:

• chr17-65537577-G-C
• rs754204017
• NM_004655.4:c.1459C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004655.4(AXIN2):​c.1459C>G​(p.Leu487Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. L487R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• 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: Ambry Genetics, ClinGen, 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15441608).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1459C>G	p.Leu487Val	missense	Exon 6 of 11	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1459C>G	p.Leu487Val	missense	Exon 6 of 10	NP_001350742.1	E7ES00

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1459C>G	p.Leu487Val	missense	Exon 6 of 11	ENSP00000302625.5	Q9Y2T1
	AXIN2	ENST00000375702.5	TSL:1	c.1459C>G	p.Leu487Val	missense	Exon 5 of 9	ENSP00000364854.5	E7ES00
	AXIN2	ENST00000881031.1		c.1459C>G	p.Leu487Val	missense	Exon 6 of 11	ENSP00000551090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239724 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457274 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 724664

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000226 AC: 1 AN: 44184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110732

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.058
Sift	Benign	0.23	T
Sift4G	Benign	0.51	T
Polyphen		0.0060	B
Vest4		0.18
MutPred		0.19		Gain of methylation at K486 (P = 0.0446)
MVP		0.62
MPC		0.18
ClinPred		0.21	T
GERP RS		4.2
gMVP		0.11
Mutation Taster		=96/4	polymorphism

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: rs754204017; hg19: chr17-63533695;