rs774732785
Variant summary
Our verdict is Likely benign. Variant got -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. 11/19 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
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.2002G>A | p.Gly668Arg | missense_variant | 8/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2002G>A | p.Gly668Arg | missense_variant | 8/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1807G>A | p.Gly603Arg | missense_variant | 6/9 | 1 | |||
AXIN2 | ENST00000618960.4 | c.1807G>A | p.Gly603Arg | missense_variant | 7/10 | 5 | |||
AXIN2 | ENST00000578251.1 | n.224G>A | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244840Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133054
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461436Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727008
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2017 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2023 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at