rs749846538
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004655.4(AXIN2):c.1222G>A(p.Glu408Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000153 in 1,572,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E408D) has been classified as Uncertain significance.
Frequency
Consequence
NM_004655.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.1222G>A | p.Glu408Lys | missense_variant | 6/11 | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.1222G>A | p.Glu408Lys | missense_variant | 6/11 | 1 | NM_004655.4 | P1 | |
AXIN2 | ENST00000375702.5 | c.1222G>A | p.Glu408Lys | missense_variant | 5/9 | 1 | |||
AXIN2 | ENST00000618960.4 | c.1222G>A | p.Glu408Lys | missense_variant | 6/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000671 AC: 13AN: 193720Hom.: 0 AF XY: 0.0000474 AC XY: 5AN XY: 105408
GnomAD4 exome AF: 0.0000127 AC: 18AN: 1420528Hom.: 0 Cov.: 36 AF XY: 0.0000142 AC XY: 10AN XY: 702456
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152024Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74238
ClinVar
Submissions by phenotype
Oligodontia-cancer predisposition syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the AXIN2 protein (p.Glu408Lys). This variant is present in population databases (rs749846538, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medulloblastoma (PMID: 17373666). ClinVar contains an entry for this variant (Variation ID: 408784). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 27, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2022 | The p.E408K variant (also known as c.1222G>A), located in coding exon 5 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 25, 2022 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 09, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medulloblastoma and absent in unaffected controls (Koch et al., 2007); This variant is associated with the following publications: (PMID: 15735151, 17373666) - |
Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
AXIN2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2023 | The AXIN2 c.1222G>A variant is predicted to result in the amino acid substitution p.Glu408Lys. This variant has been reported in a medulloblastoma specimen (Koch et al. 2007. PubMed ID: 17373666). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-63533932-C-T/?dataset=gnomad_r2_1). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/408784/). 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