About AXIN2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AXIN2 c.1908-23C>T, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_004655.4:c.1908-23C>T is present in gnomAD at extremely low frequency: v2.1 AF = 0.00109% (3/274,000 alleles), v4.1 AF = 0.00037% (6/1,611,554 alleles), with no homozygotes observed. Both frequencies are well below the 0.1% PM2 threshold for dominant disorders. However, the variant is a deep intronic substitution with no predicted splicing impact (SpliceAI delta = 0.00), which limits the weight of population rarity as evidence of pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,611,554 alleles
gnomAD v4.1: 6 / 1,611,554 alleles. Recorded AF 3.72311e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.09489e-05; MAF= 0.00109%, 3/274000 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.46285e-05; MAF= 0.00246%, 3/121810 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 17 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004655.4:c.1908-23C>T is a deep intronic variant in AXIN2 located 23 bp upstream of exon 7.
SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), providing no computational evidence of altered splicing.
The variant is present in gnomAD at extremely low frequency: v2.1 AF = 0.00109% (3/274,000 alleles) and v4.1 AF = 0.00037% (6/1,611,554 alleles), with no homozygotes observed (PM2_supporting). However, rarity alone is limited by the absence of a predicted functional consequence.
This variant is absent from ClinVar, and no publications, functional studies, segregation data, or de novo observations are available.
AXIN2 loss of function is a recognized germline disease mechanism associated with colorectal polyposis and tooth agenesis, but no variant-specific evidence exists to support pathogenicity of this deep intronic substitution.
Based on the generic ACMG/AMP 2015 classification framework, the available evidence (PM2_supporting only) is insufficient to classify this variant as pathogenic or likely pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingNM_004655.4:c.1908-23C>T is present in gnomAD at extremely low frequency: v2.1 AF = 0.00109% (3/274,000 alleles), v4.1 AF = 0.00037% (6/1,611,554 alleles), with no homozygotes observed. Both frequencies are well below the 0.1% PM2 threshold for dominant disorders. However, the variant is a deep intronic substitution with no predicted splicing impact (SpliceAI delta = 0.00), which limits the weight of population rarity as evidence of pathogenicity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 1.09e-05 (3/274
- 000)
- v4.1 AF = 3.72e-06 (6/1
- 611
- 554)
- no homozygotes
- grpmax FAF = 3.12e-06 (v2.1)
- 1.24e-06 (v4.1).
Still missing
- No predicted functional consequence (SpliceAI delta = 0.00)
- rarity alone may not indicate pathogenicity for a deep intronic variant.
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No known pathogenic variant has been reported at this nucleotide position (c.1908-23) in ClinVar or the literature. PS1 requires a known pathogenic variant at the same nucleotide position. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same-nucleotide pathogenic comparator exists.
Sources
PS2 No de novo observation has been reported for this variant. PS2 requires confirmation of de novo occurrence in a patient with disease and no family history. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar or the literature.
Still missing
- No de novo testing has been performed for this variant.
PS3 No functional studies have been performed on NM_004655.4:c.1908-23C>T. The variant has not been directly tested in any experimental assay, nor does it fall within a systematically characterized range. No REVEL or BayesDel scores are available for this intronic variant. Details ▾Hide ▴
Evidence considered
- No functional data
- no in silico structural predictions
- no publications found for this variant.
Still missing
- No functional characterization of this deep intronic variant has been performed.
PS4 No case-control or statistical enrichment data are available for this variant. PS4 requires significantly increased prevalence in affected individuals compared to controls. Details ▾Hide ▴
Evidence considered
- No case-control studies or cohort data identified for this variant.
Still missing
- No affected vs. control prevalence data exist.
PM1 NM_004655.4:c.1908-23C>T is located in intron 7, 23 bp upstream of the exon boundary. SpliceAI predicts no splicing impact (max delta = 0.00), so there is no evidence that this variant disrupts a critical functional domain. PM1 requires the variant to reside in a mutational hotspot or critical functional domain. Details ▾Hide ▴
Evidence considered
- Deep intronic location
- SpliceAI delta = 0.00 (no predicted splice alteration)
- not in a known functional domain.
Sources
PM6 No de novo observation has been reported for this variant. PM6 requires confirmation of de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No de novo testing data.
PP1 No segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No segregation analysis performed.
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No HCI prior probability is available for AXIN2. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splicing effect)
- REVEL/BayesDel not available (intronic)
- HCI prior not supported for AXIN2.
Sources
PP4 No phenotype or clinical data are available for the individual(s) carrying this variant. PP4 requires the patient's phenotype or family history to be highly specific for the disease associated with the gene. Details ▾Hide ▴
Evidence considered
- No phenotype information provided for this case.
Still missing
- Patient phenotype not available.
BA1 The highest observed population allele frequency is 0.00246% (NFE, gnomAD v2.1), which is well below the 1% BA1 threshold. The variant does not qualify as a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF = 0.00246% (NFE)
- v4.1 max subpopulation AF = 0.00160% (Remaining)
- well below 1% BA1 threshold.
Sources
BS1 The highest observed population allele frequency is 0.00246% (NFE, gnomAD v2.1), which is well below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF = 0.00246%
- v4.1 max subpopulation AF = 0.00160%
- well below 0.3% BS1 threshold.
Sources
BS2 No data are available on observation of this variant in healthy adults for a fully penetrant dominant disorder. The gnomAD observations (3 heterozygous in v2.1, 6 heterozygous in v4.1) do not include phenotype data. Details ▾Hide ▴
Evidence considered
- gnomAD carriers lack phenotype annotation
- insufficient to assess BS2 in the absence of clinical context.
Still missing
- No phenotype data for gnomAD carriers.
BS3 No functional studies demonstrating no deleterious effect have been performed on this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. Details ▾Hide ▴
Evidence considered
- No functional studies available for this variant.
Still missing
- No functional characterization performed.
BS4 No segregation data are available. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data available.
Still missing
- No segregation analysis performed.
BP2 No data available on co-occurrence with a known pathogenic variant. BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic variant for a fully penetrant recessive disorder. Details ▾Hide ▴
Evidence considered
- No co-occurrence data available.
Still missing
- No phase or co-occurrence data.
BP4 SpliceAI predicts no splicing impact (max delta = 0.00) for this deep intronic variant. However, BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI is available for this intronic variant; REVEL and BayesDel are not applicable. A single line of evidence does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- single computational line available
- REVEL/BayesDel not applicable for intronic variants.
Still missing
- No additional computational tools applicable for intronic variants beyond SpliceAI.
Sources
PS5 PS5 requires a reputable source (e.g., clinical diagnostic laboratory) to have previously classified this variant as pathogenic. This variant is absent from ClinVar and has no prior clinical classifications. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no prior pathogenic classification exists.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004655.4:c.1908-23C>T is a deep intronic substitution located 23 bp upstream of exon 7. It does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant class is intronic (bucket: other)
- does not meet PVS1 decision tree entry criteria per PMC6185798.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/AThis is an intronic variant with no protein change; no same-residue pathogenic missense comparator can be identified. PM5 requires a different amino acid change at the same residue classified as pathogenic. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json confirms no residue context available for PM5 comparison
- intronic variant.
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a missense variant. Details ▾Hide ▴
Evidence considered
- Intronic variant
- PP2 is restricted to missense changes.
PP5 N/AThis variant is absent from ClinVar. PP5 requires a ClinVar entry from a reputable source (at least 3-star expert panel) classifying the variant as pathogenic. No ClinVar record exists for this variant. Details ▾Hide ▴
BP1 N/ABP1 applies specifically to missense variants in genes where truncating variants are the primary pathogenic mechanism. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a missense variant. Details ▾Hide ▴
Evidence considered
- Intronic variant
- BP1 is restricted to missense changes.
BP3 N/ASkipped — trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
BP5 N/AThis variant is absent from ClinVar. BP5 requires a ClinVar record from a reputable source classifying the variant as benign or likely benign. No ClinVar entry exists. Details ▾Hide ▴
BP6 N/AThis variant is absent from ClinVar. BP6 requires a ClinVar entry from a reputable source (at least 3-star expert panel) classifying the variant as benign. No ClinVar record exists. Details ▾Hide ▴
BP7 N/ABP7 applies specifically to synonymous coding variants for which splicing prediction algorithms predict no impact. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a coding synonymous variant. Details ▾Hide ▴
Evidence considered
- Intronic variant
- BP7 is restricted to synonymous coding changes.
Identifiers
- Gene
- AXIN2
- Transcript
- NM_004655.4
- Coding (HGVS c.)
- NM_004655.4:c.1908-23C>T
- Protein (HGVS p.)
- NP_004646.3:p.?
- GRCh38
- chr17:65536576 G>A
- GRCh37
- chr17:63532694 G>A
Gene diagram
Every interpreted variant in AXIN2, mapped onto the exon structure of NM_004655.4. Select a row to find it on the plot.
AXIN2NM_004655.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in AXIN2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
6 / 1,611,554 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
3 / 274,000 alleles
AF 1.09e-05 · 0 homozygotes · FAF 3.12e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,611,554 alleles · 0 hom · FAF 1.2e-06
| Remaining individuals1 / 62,402 | 1.6e-05 |
| European (non-Finnish)5 / 1,178,300 | 4.2e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 3 / 274,000 alleles · 0 hom · FAF 3.1e-06
| European (non-Finnish)3 / 121,810 | 2.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.72311e-06; MAF= 0.00037%, 6/1611554 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60251e-05; MAF= 0.00160%, 1/62402 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.09489e-05; MAF= 0.00109%, 3/274000 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.46285e-05; MAF= 0.00246%, 3/121810 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No HCI prior probability is available for AXIN2. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no predicted splicing effect)
- REVEL/BayesDel not available (intronic)
- HCI prior not supported for AXIN2.
Sources
BP4 SpliceAI predicts no splicing impact (max delta = 0.00) for this deep intronic variant. However, BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI is available for this intronic variant; REVEL and BayesDel are not applicable. A single line of evidence does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- single computational line available
- REVEL/BayesDel not applicable for intronic variants.
Still missing
- No additional computational tools applicable for intronic variants beyond SpliceAI.
Sources
BP7 N/ABP7 applies specifically to synonymous coding variants for which splicing prediction algorithms predict no impact. NM_004655.4:c.1908-23C>T is a deep intronic substitution, not a coding synonymous variant. Details ▾Hide ▴
Evidence considered
- Intronic variant
- BP7 is restricted to synonymous coding changes.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,611,554 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004655.4%3Ac.1908-23C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-63532694-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-65536576-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-65536576-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004655.4%3Ac.1908…
- OncoKB ↗www.oncokb.org/gene/AXIN2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=AXIN2+c.1908-23C%3ET
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.72311e-06; MAF= 0.00037%, 6/1611554 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60251e-05; MAF= 0.00160%, 1/62402 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.09489e-05; MAF= 0.00109%, 3/274000 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.46285e-05; MAF= 0.00246%, 3/121810 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).