17-65536315-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_004655.4(AXIN2):c.2141+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,605,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004655.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AXIN2 | NM_004655.4 | c.2141+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000307078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AXIN2 | ENST00000307078.10 | c.2141+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_004655.4 | P1 | |||
AXIN2 | ENST00000375702.5 | c.1946+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | |||||
AXIN2 | ENST00000618960.4 | c.1946+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | |||||
AXIN2 | ENST00000578251.1 | n.363+5G>A | splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152264Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000175 AC: 4AN: 228272Hom.: 0 AF XY: 0.0000161 AC XY: 2AN XY: 124124
GnomAD4 exome AF: 0.00000550 AC: 8AN: 1453522Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4AN XY: 722434
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74394
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2023 | - - |
Oligodontia-cancer predisposition syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | 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 (rs769868369, gnomAD 0.006%). 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: 464596). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | Mar 21, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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 | May 03, 2023 | The c.2141+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the AXIN2 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at