rs376613525
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_004655.4(AXIN2):c.2141+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000934 in 1,606,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
AXIN2
NM_004655.4 splice_donor_region, intron
NM_004655.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9983
2
Clinical Significance
Conservation
PhyloP100: 2.00
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
?
High AC in GnomAdExome at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.2141+4A>G | splice_donor_region_variant, intron_variant | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2141+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_004655.4 | P1 | |||
AXIN2 | ENST00000375702.5 | c.1946+4A>G | splice_donor_region_variant, intron_variant | 1 | |||||
AXIN2 | ENST00000618960.4 | c.1946+4A>G | splice_donor_region_variant, intron_variant | 5 | |||||
AXIN2 | ENST00000578251.1 | n.363+4A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000392 AC: 9AN: 229390Hom.: 0 AF XY: 0.0000481 AC XY: 6AN XY: 124752
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GnomAD4 exome AF: 0.00000963 AC: 14AN: 1454232Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9AN XY: 722828
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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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change falls in intron 8 of the AXIN2 gene. It does not directly change the encoded amino acid sequence of the AXIN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376613525, gnomAD 0.01%). 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: 419353). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2022 | In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2023 | The c.2141+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 7 in the AXIN2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
AXIN2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2023 | The AXIN2 c.2141+4A>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-63532434-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/419353/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at