rs774732785

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004655.4(AXIN2):c.2002G>A(p.Gly668Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G668A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.872

Publications

0 publications found

Variant links:

COSMIC-nc: COSV61056046

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

AXIN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4 link	c.2002G>A	p.Gly668Arg	missense_variant	Exon 8 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AXIN2	ENST00000307078.10 link	c.2002G>A	p.Gly668Arg	missense_variant	Exon 8 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5 link	c.1807G>A	p.Gly603Arg	missense_variant	Exon 6 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4 link	c.1807G>A	p.Gly603Arg	missense_variant	Exon 7 of 10	5		ENSP00000478916.1
AXIN2	ENST00000578251.1 link	n.224G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

244840

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000379

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome

Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 668 of the AXIN2 protein (p.Gly668Arg). This variant is present in population databases (rs774732785, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420080). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AXIN2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Colorectal cancer

Uncertain:1

Aug 05, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 09, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted AXIN2 c.2002G>A at the cDNA level, p.Gly668Arg (G668R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an endometrial carinoma (Jones 2014). AXIN2 Gly668Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. AXIN2 Gly668Arg occurs at a position that is conserved through mammals and is located in the mutational hotspot (Salahshor 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether AXIN2 Gly668Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G668R variant (also known as c.2002G>A), located in coding exon 7 of the AXIN2 gene, results from a G to A substitution at nucleotide position 2002. The glycine at codon 668 is replaced by arginine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Benign

-0.85

PhyloP100

0.87

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.71

N;.;N

REVEL

Benign

0.13

Sift

Benign

0.074

T;.;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.99

.;D;D

Vest4

0.51

MutPred

0.16

Gain of MoRF binding (P = 0.0124);.;.;

MVP

0.61

MPC

0.69

ClinPred

0.55

GERP RS

4.3

gMVP

0.24

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over