17-65558568-C-G

Variant names:

• chr17-65558568-C-G
• rs878854732
• NM_004655.4:c.53G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004655.4(AXIN2):​c.53G>C​(p.Arg18Pro) 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. 12/20 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. R18H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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

ENSG00000266076 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27410984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5
ENSG00000266076	ENST00000577662.1	n.*229G>C		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000462418.1
ENSG00000266076	ENST00000577662.1	n.*229G>C		3_prime_UTR_variant	Exon 4 of 7	2		ENSP00000462418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Jan 09, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with proline at codon 18 of the AXIN2 protein (p.Arg18Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a AXIN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Benign	0.38	.;.;T;T;T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	.;D;D;.;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D;.;.;N;.;.;.;D
REVEL	Benign	0.28
Sift	Benign	0.19	T;.;.;T;.;.;.;D
Sift4G	Uncertain	0.058	T;D;T;T;.;.;.;.
Polyphen		0.84	.;.;P;P;.;.;.;.
Vest4		0.65
MutPred		0.15		Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);Gain of glycosylation at S15 (P = 0.0538);
MVP		0.46
MPC		0.83
ClinPred		0.97	D
GERP RS		1.6
PromoterAI		-0.070	Neutral
gMVP		0.50
Mutation Taster		=69/31	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: rs878854732; hg19: chr17-63554686;