chr17-65535693-T-C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2
The NM_004655.4(AXIN2):c.2170A>G(p.Arg724Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R724T) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
Publications
- oligodontia-cancer predisposition syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
- tooth agenesisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- craniosynostosisInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2170A>G | p.Arg724Gly | missense_variant | Exon 9 of 11 | 1 | NM_004655.4 | ENSP00000302625.5 | ||
AXIN2 | ENST00000375702.5 | c.1975A>G | p.Arg659Gly | missense_variant | Exon 7 of 9 | 1 | ENSP00000364854.5 | |||
AXIN2 | ENST00000618960.4 | c.1975A>G | p.Arg659Gly | missense_variant | Exon 8 of 10 | 5 | ENSP00000478916.1 | |||
AXIN2 | ENST00000578251.1 | n.392A>G | non_coding_transcript_exon_variant | Exon 2 of 3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251380 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727240 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.R724G variant (also known as c.2170A>G), located in coding exon 8 of the AXIN2 gene, results from an A to G substitution at nucleotide position 2170. The arginine at codon 724 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Oligodontia-cancer predisposition syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 724 of the AXIN2 protein (p.Arg724Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 533156). 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
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AXIN2-related disorder Uncertain:1
The AXIN2 c.2170A>G variant is predicted to result in the amino acid substitution p.Arg724Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/533156/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at