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AXIN2c.405C>TUncertain significance
Print report
Variant interpretation report

AXIN2 c.405C>T, p.(Tyr135=)

NM_004655.4:c.405C>T NP_004646.3:p.(Tyr135=) Synonymous · exon 2 View identifiers
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.

About AXIN2

AXIN2 is a scaffolding protein that helps regulate the Wnt signaling pathway, a key developmental pathway controlling cell growth and fate. It is part of the beta-catenin destruction complex, where it helps mark beta-catenin for degradation when Wnt signaling is off, and it also assists in relaying Wnt signals to the nucleus when the pathway is active. AXIN2 acts as a tumor suppressor, and mutations in the gene have been linked to colorectal cancer as well as familial tooth agenesis with predisposition to colorectal cancer. Its expression has also been associated with prostate cancer recurrence.

NCBI Gene ↗ OncoKB ↗
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met (supporting): extremely rare in gnomAD v4.1 at 0.00719% allele frequency (116/1,613,976 alleles) with zero homozygotes.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met (supporting): SpliceAI max delta 0.00 is below the 0.10 benign threshold, indicating no splice impact.

Recorded classification: Uncertain significance

Generic ACMG/AMP 2015 rules were applied (no AXIN2-specific framework available); PM2-supporting plus BP4-supporting reaches no pathogenic or benign threshold, so the variant is classified 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
116 / 1,613,976 alleles

gnomAD v4.1: 116 / 1,613,976 alleles. Recorded AF 7.18722e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59051e-05; MAF= 0.00159%, 4/251492 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51599e-05; MAF= 0.00352%, 4/113766 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions

4 Likely benign · 1 Benign · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 5 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

Population evidence supports PM2 at supporting strength. BA1 and BS1 are not met because the observed frequencies are far below stand-alone benign or disorder-inconsistent levels, and BS2 is not assessed because no phenotype-verified healthy adult carrier evidence is available.

Met · 2

PM2 SupportingMet (supporting): extremely rare in gnomAD v4.1 at 0.00719% allele frequency (116/1,613,976 alleles) with zero homozygotes. Details ▾Hide ▴
Reasoning

PM2 is met at supporting strength under the generic ACMG/AMP fallback. The variant is extremely rare in population databases: gnomAD v4.1 reports 116/1,613,976 alleles (AF 0.00719%), zero homozygotes, and joint grpmax FAF 0.00809%; gnomAD v2.1 reports 4/251,492 alleles (AF 0.00159%), also with zero homozygotes. It is absent from gnomAD-Canada v1.0. The nonzero observations mean the variant must not be described as completely absent from population databases, but the frequency is compatible with rare disease-associated variation and supports rarity-based PM2 at supporting strength.

Rule
Generic ACMG/AMP PM2: absence from controls or presence only at an extremely low frequency not inconsistent with the disorder supports rarity evidence; because the variant is observed at a low nonzero frequency and no disease-calibrated AXIN2 threshold is available, supporting strength is used.
Evidence considered
  • gnomAD v4.1 reports 116/1,613,976 alleles (AF 0.00719%), zero homozygotes, European (non-Finnish) maximum 113/1,180,024 alleles (AF 0.00958%), and joint grpmax FAF 0.00809%.
  • gnomAD v2.1 reports 4/251,492 alleles (AF 0.00159%), zero homozygotes, European (non-Finnish) maximum 4/113,766 alleles (AF 0.00352%), and grpmax FAF 0.00112%.
  • The variant is absent from gnomAD-Canada v1.0.
  • No AXIN2-specific VCEP/CSPEC or local gene-specific framework was retrieved; generic ACMG/AMP fallback is therefore governing.
Still missing
  • No AXIN2-specific PM2 threshold or penetrance-calibrated maximum credible allele frequency was available because no VCEP/CSPEC or local gene-specific framework was retrieved.
  • The disease prevalence and penetrance model for the relevant AXIN2-associated disorder were not provided, limiting disease-specific strength calibration.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rules
BP4 SupportingMet (supporting): SpliceAI max delta 0.00 is below the 0.10 benign threshold, indicating no splice impact. Details ▾Hide ▴
Reasoning

AXIN2 NM_004655.4:c.405C>T is synonymous (p.Tyr135=). In the absence of an AXIN2-specific specification, the generic non-missense SpliceAI path applies. SpliceAI max delta is 0.00, below the calibrated benign threshold (<0.10), supporting no splice impact; BP4 is met at supporting strength.

Rule
Generic non-missense PP3/BP4 splice-prediction fallback: SpliceAI max delta <0.10 supports BP4; do not combine splice and missense computational paths.
Evidence considered
  • No governing AXIN2 CSPEC, VCEP material, or gene-specific PP3/BP4 lookup was retrieved; generic ACMG/AMP fallback is therefore applicable.
  • SpliceAI Lookup reports no significant splice impact and max delta score 0.00 for NM_004655.4:c.405C>T. The generic fallback assigns non-missense variants to the SpliceAI path and defines BP4 at max delta <0.10.
  • Published computational-evidence calibration: PMID 36413997 supports use of SpliceAI <=0.10 for supporting benign computational evidence and >=0.20 for supporting pathogenic computational evidence; the observed score supports BP4.
Sources
spliceai ↗generic_acmg_combination_rules

Not met · 5 · evaluated, threshold not reached

PP3 Not met: SpliceAI max delta 0.00 vs the >0.20 pathogenic-evidence threshold. Details ▾Hide ▴
Reasoning

AXIN2 NM_004655.4:c.405C>T is synonymous (p.Tyr135=). With no AXIN2 VCEP specification available, the generic non-missense splice-prediction path applies. SpliceAI max delta is 0.00, below the pathogenic-evidence threshold (>0.20); PP3 is not met.

Rule
Generic non-missense PP3/BP4 splice-prediction fallback: SpliceAI max delta >0.20 supports PP3; do not combine splice and missense computational paths.
Evidence considered
  • No governing AXIN2 CSPEC, VCEP material, or gene-specific PP3/BP4 lookup was retrieved; generic ACMG/AMP fallback is therefore applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_004655.4:c.405C>T. The generic fallback assigns non-missense variants to the SpliceAI path and defines PP3 at max delta >0.20.
  • Published computational-evidence calibration: PMID 36413997 supports use of SpliceAI <=0.10 for supporting benign computational evidence and >=0.20 for supporting pathogenic computational evidence; the observed score does not support PP3.
Sources
spliceai ↗generic_acmg_combination_rules
PP5 Not met: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this exact variant. Details ▾Hide ▴
Reasoning

No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is present for AXIN2 c.405C>T (Variation ID 464621).

Rule
PP5 is restricted to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • The exact ClinVar record has six laboratory submissions (Likely benign, Benign, and Uncertain significance) and its expert_panels field is empty. Ordinary laboratory assertions and aggregate labels were not used for PP5.
Sources
clinvar ↗
BA1 Not met: highest population frequency 0.00958% (gnomAD v4.1) is far below a stand-alone benign threshold. Details ▾Hide ▴
Reasoning

BA1 is not met. The variant is rare in the available population datasets: gnomAD v4.1 reports 116/1,613,976 alleles (AF 0.00719%), with the highest listed population frequency in European (non-Finnish) individuals at 113/1,180,024 alleles (AF 0.00958%) and joint grpmax FAF 0.00809%. These frequencies are far below a stand-alone benign threshold. The variant is absent from gnomAD-Canada v1.0, which does not provide evidence for BA1.

Rule
Generic ACMG/AMP BA1: a population allele frequency above the stand-alone benign threshold is required; the observed frequencies do not meet that requirement.
Evidence considered
  • gnomAD v4.1 reports 116/1,613,976 total alleles (AF 0.00719%), zero homozygotes, and a highest listed frequency of 113/1,180,024 alleles (AF 0.00958%) in the European (non-Finnish) population; joint grpmax FAF is 0.00809%.
  • gnomAD v2.1 reports 4/251,492 alleles (AF 0.00159%) with zero homozygotes; the highest listed European (non-Finnish) subgroup frequency is 4/113,766 alleles (AF 0.00352%).
  • The variant is absent from gnomAD-Canada v1.0.
  • No AXIN2-specific VCEP/CSPEC or local gene-specific framework was retrieved; generic ACMG/AMP fallback is therefore governing.
Still missing
  • No AXIN2-specific population-frequency threshold or penetrance-calibrated maximum credible allele frequency was available because no VCEP/CSPEC or local gene-specific framework was retrieved.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗generic_acmg_combination_rules
BS1 Not met: allele frequency 0.00719% does not exceed expected levels for a rare AXIN2-associated disorder. Details ▾Hide ▴
Reasoning

BS1 is not met. gnomAD v4.1 shows an overall allele frequency of 0.00719%, a highest listed subgroup frequency of 0.00958% in European (non-Finnish) individuals, and joint grpmax FAF of 0.00809%. These values are not greater than expected for a rare AXIN2-associated disorder, even allowing for uncertain or reduced penetrance. The observations are not an ancestry-specific elevation sufficient to support a benign-frequency criterion.

Rule
Generic ACMG/AMP BS1: the allele frequency must be greater than expected for the disorder; the observed frequency is extremely low and does not meet that condition.
Evidence considered
  • gnomAD v4.1 reports 116/1,613,976 total alleles (AF 0.00719%) and the highest listed subgroup frequency of 113/1,180,024 alleles (AF 0.00958%) in European (non-Finnish) individuals; joint grpmax FAF is 0.00809%.
  • gnomAD v2.1 reports 4/251,492 alleles (AF 0.00159%) and a European (non-Finnish) subgroup frequency of 4/113,766 alleles (AF 0.00352%).
  • The variant is observed predominantly in the European (non-Finnish) population in both datasets, but the allele counts and frequencies remain very low and do not indicate a population-frequency artifact supporting BS1.
  • No AXIN2-specific VCEP/CSPEC or local gene-specific framework was retrieved; generic ACMG/AMP fallback is therefore governing.
Still missing
  • No AXIN2-specific disease prevalence, penetrance estimate, or maximum credible allele frequency was available to provide a gene- and disorder-calibrated BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗generic_acmg_combination_rules
BP6 Not met: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant. Details ▾Hide ▴
Reasoning

No exact-variant ClinVar expert-panel Benign or Likely benign assertion is present for AXIN2 c.405C>T (Variation ID 464621).

Rule
BP6 is restricted to an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
  • The exact ClinVar record has six laboratory submissions (Likely benign, Benign, and Uncertain significance) and its expert_panels field is empty. Ordinary laboratory assertions and aggregate labels were not used for BP6.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 Not assessed: no de novo occurrence with confirmed parentage was documented. Details ▾Hide ▴
Reasoning

No proband-level de novo evidence is documented in the case-evidence bundle. There is no documented phenotype-consistent affected proband, confirmed maternity and paternity, or parental testing showing the variant absent in both biological parents. The variant is synonymous (NP_004646.3:p.(Y135=)), but that does not establish or exclude de novo occurrence.

Rule
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; stronger evidence requires additional confirmation and/or multiple well-documented observations. No case-level data satisfy assessment.
Evidence considered
  • The consolidated case-evidence bundle contains no proband, parental-testing, trio, or de novo observation for NM_004655.4:c.405C>T.
  • The bundle identifies the variant as NM_004655.4:c.405C>T with predicted protein consequence NP_004646.3:p.(Y135=); this annotation is not evidence of de novo status.
  • No AXIN2-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback was therefore used for criterion interpretation.
Still missing
  • Proband phenotype and clinical indication are not documented for this variant.
  • No parental genotypes or confirmed maternity/paternity are provided.
  • No trio testing, parental-absence result, or de novo confirmation is provided.
PS3 Not assessed: no functional assay demonstrating a disease-relevant effect of this variant was available. Details ▾Hide ▴
Reasoning

No validated functional assay demonstrating a disease-relevant deleterious effect of NM_004655.4:c.405C>T (NP_004646.3:p.(Y135=)) was identified in the case evidence bundle. The available extracted publications do not report this AXIN2 variant or variant-specific functional data.

Rule
PS3 requires well-established functional studies appropriate to the disease mechanism and relevant to the exact variant; strength cannot be assigned without validated variant-specific assay evidence.
Evidence considered
  • The case bundle identifies no gene-specific VCEP/CSPEC framework for AXIN2, so generic ACMG/AMP functional-evidence principles were used.
  • The extracted record for PMID:25394175 states that the paper does not report AXIN2, c.405C>T, p.(Y135=), or variant-specific functional data.
  • The extracted record for PMID:26467025 states that the paper describes a general variant-scoring system and provides no AXIN2-specific assay or observation for c.405C>T.
Still missing
  • A disease-relevant functional assay for the exact variant is not available.
  • Assay controls, replicate data, quantitative effect size, and validation against known pathogenic and benign controls are not available.
Sources
PMID:25394175 ↗PMID:26467025 ↗
PS4 Not assessed: no affected-case series or case-control data for this variant were provided. Details ▾Hide ▴
Reasoning

No variant-specific affected-case series, case-control comparison, or statistically supported enrichment data were provided for AXIN2 c.405C>T (p.Tyr135=).

Rule
Generic ACMG/AMP fallback: PS4 requires a statistically increased prevalence of the variant in affected individuals compared with controls.
Evidence considered
  • The available literature triage contains only general guidelines or laboratory-method papers; neither fetched full-text extraction mentions AXIN2 c.405C>T or p.(Tyr135=).
Still missing
  • Variant-specific affected and control allele counts from a defined, phenotypically relevant cohort, with an appropriate statistical comparison.
PM3 Not assessed: no second pathogenic variant in trans or other inheritance data were documented. Details ▾Hide ▴
Reasoning

No applicable AXIN2-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework is used. The evidence bundle contains no affected-proband observations, second pathogenic or likely pathogenic AXIN2 variant, phase determination, parental testing, or other inheritance data demonstrating this variant in trans with a pathogenic variant in an affected individual. PM3 therefore cannot be assessed.

Evidence considered
  • The case summary identifies the variant as NM_004655.4:c.405C>T (NP_004646.3:p.(Tyr135=)) in AXIN2 and reports no CSPEC/VCEP framework.
  • The consolidated evidence bundle provides no affected-proband, compound-heterozygous, trans/cis phase, segregation, or parental-testing observation for this variant.
  • The available paper extracts are not variant-specific and provide no AXIN2 allelic evidence relevant to PM3.
Still missing
  • Affected-proband case data are absent.
  • No pathogenic or likely pathogenic AXIN2 allele for comparison is documented.
  • No phasing or parental-inheritance data establish a trans configuration.
  • AXIN2 inheritance and disease-relevant biallelic evidence for this case are not documented.
PM6 Not assessed: no suspected de novo occurrence with parental testing was reported. Details ▾Hide ▴
Reasoning

No suspected de novo occurrence is reported in the case-evidence bundle. There is no documented affected proband with the variant and no parental testing, maternity/paternity confirmation, or phenotype-consistent clinical report supporting PM6.

Rule
Generic ACMG/AMP PM6: assumed de novo occurrence when maternity and paternity are unconfirmed. A de novo assertion still requires a documented clinical observation and appropriate phenotype/context; neither is available here.
Evidence considered
  • The case-evidence bundle provides no suspected de novo report for NM_004655.4:c.405C>T.
  • The available paper extracts explicitly indicate that the fetched papers do not report AXIN2 or this specific variant; they therefore provide no de novo or parental evidence.
  • No AXIN2-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback was therefore used for criterion interpretation.
Still missing
  • No clinical case description or phenotype is provided.
  • No parental testing or parentage confirmation is provided.
  • No published or case-specific suspected de novo observation is available.
PP1 Not assessed: no family segregation or co-segregation analysis was documented. Details ▾Hide ▴
Reasoning

No family segregation data are documented. The bundle contains no affected or unaffected relatives, informative meioses, familial genotypes, or phenotype-consistent co-segregation analysis for NM_004655.4:c.405C>T.

Rule
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members, with strength determined by the number and informativeness of meioses. No segregation data are available for assessment.
Evidence considered
  • The consolidated case-evidence bundle contains no segregation observations for NM_004655.4:c.405C>T.
  • The paper extracts for all fetched papers contain no AXIN2-specific or variant-specific familial segregation findings.
  • No AXIN2-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback was therefore used for criterion interpretation.
Still missing
  • No family pedigree or number of informative meioses is provided.
  • No genotypes for affected or unaffected relatives are provided.
  • No assessment of phenotype consistency, penetrance, or age-related expression is provided.
PP4 Not assessed: no individual-level phenotype or diagnostic workup was provided. Details ▾Hide ▴
Reasoning

No individual-level phenotype, diagnostic workup, or phenotype-to-genotype specificity evidence was provided for the carrier of this variant.

Rule
Generic ACMG/AMP fallback: PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
  • ClinVar condition labels are submission-level labels and do not provide a variant-carrier phenotype or diagnostic specificity assessment.
Still missing
  • A documented patient phenotype and exclusion of alternative genetic or non-genetic causes sufficient to establish a highly specific AXIN2-associated presentation.
BS2 Not assessed: no phenotype-verified healthy adult carriers were documented. Details ▾Hide ▴
Reasoning

BS2 cannot be assessed from the supplied evidence. The population datasets report zero homozygotes, but allele counts alone do not demonstrate that carriers are healthy adults. No phenotype-verified adult carriers, age-of-onset information, penetrance estimate, or disease-status assessment for this exact variant is provided.

Rule
Generic ACMG/AMP BS2: the exact variant must be observed in healthy adults in a disorder expected to be fully penetrant at an early age; unphenotyped population allele counts are insufficient.
Evidence considered
  • gnomAD v4.1 reports zero homozygotes among 1,613,976 alleles; gnomAD v2.1 reports zero homozygotes among 251,492 alleles.
  • The presence of heterozygous alleles in population databases does not establish healthy adult status, because the records do not provide individual phenotype, age, or penetrance information for this exact variant.
Still missing
  • Phenotype-verified healthy adult carriers of the exact variant are needed.
  • AXIN2-associated disease penetrance, age of onset, inheritance model, and ascertainment context are needed to determine whether an unaffected adult carrier would be informative for BS2.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no functional assay evidence of no damaging effect was available. Details ▾Hide ▴
Reasoning

No validated functional assay demonstrating that NM_004655.4:c.405C>T (NP_004646.3:p.(Y135=)) has no damaging effect was identified in the case evidence bundle. The available extracted publications do not report this AXIN2 variant or variant-specific functional data.

Rule
BS3 requires well-established functional studies appropriate to the disease mechanism showing no damaging effect for the exact variant; strength cannot be assigned without validated variant-specific assay evidence.
Evidence considered
  • The case bundle identifies no gene-specific VCEP/CSPEC framework for AXIN2, so generic ACMG/AMP functional-evidence principles were used.
  • The extracted record for PMID:25394175 states that the paper does not report AXIN2, c.405C>T, p.(Y135=), or variant-specific functional data.
  • The extracted record for PMID:26467025 states that the paper describes a general variant-scoring system and provides no AXIN2-specific assay or observation for c.405C>T.
Still missing
  • A disease-relevant functional assay showing a normal or benign effect for the exact variant is not available.
  • Assay controls, replicate data, quantitative effect size, and validation against known pathogenic and benign controls are not available.
Sources
PMID:25394175 ↗PMID:26467025 ↗
BS4 Not assessed: no tested unaffected carriers or non-segregation data were documented. Details ▾Hide ▴
Reasoning

No non-segregation evidence is documented. The case-evidence bundle does not identify unaffected relatives who were tested and found to carry NM_004655.4:c.405C>T, nor does it provide sufficient family structure, ages, phenotypes, or penetrance information to establish lack of segregation.

Rule
Generic ACMG/AMP BS4: lack of segregation in affected members of a family. Application requires informative familial testing and phenotype assessment; these data are absent.
Evidence considered
  • The consolidated case-evidence bundle contains no familial non-segregation observation for NM_004655.4:c.405C>T.
  • Population frequency, ClinVar classifications, and the synonymous consequence are not substitutes for direct family non-segregation evidence and were not used for BS4.
  • No AXIN2-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback was therefore used for criterion interpretation.
Still missing
  • No tested unaffected relatives or familial variant results are provided.
  • No family structure or informative meioses are provided.
  • No age- and phenotype-appropriate evaluation of unaffected carriers is provided.
BP2 Not assessed: no phase information or co-occurrence with a pathogenic variant was documented. Details ▾Hide ▴
Reasoning

No applicable AXIN2-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework is used. The evidence bundle contains no documented pathogenic variant in trans or cis with NM_004655.4:c.405C>T, no reliable phase information, and no inheritance-mode-specific co-occurrence observation. BP2 therefore cannot be assessed.

Evidence considered
  • The case summary identifies the variant as NM_004655.4:c.405C>T (NP_004646.3:p.(Tyr135=)) in AXIN2 and reports no CSPEC/VCEP framework.
  • The consolidated evidence bundle provides no co-occurrence, phase, parental, segregation, or affected-proband observation relevant to BP2.
  • ClinVar records classifications for the exact variant but do not provide a documented pathogenic comparator allele or phase observation usable for BP2.
  • The available paper extracts are not variant-specific and provide no AXIN2 allelic evidence relevant to BP2.
Still missing
  • No pathogenic or likely pathogenic comparator variant is documented in the same individual or family.
  • No phase information establishes cis or trans configuration.
  • No inheritance-mode and penetrance context is available to determine whether a cis/trans observation would satisfy BP2.
BP5 Not assessed: no alternate molecular diagnosis was documented in the variant carrier. Details ▾Hide ▴
Reasoning

No case-level evidence documents an alternate molecular diagnosis that fully explains the observed phenotype in a carrier of this variant.

Rule
Generic ACMG/AMP fallback: BP5 requires an alternate molecular basis for disease in a case carrying the variant.
Still missing
  • Case-level phenotype and testing results demonstrating a definitive alternative molecular diagnosis that explains the presentation.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: this synonymous variant produces no null allele, so no nonsense-mediated decay or loss-of-function mechanism is triggered. Details ▾Hide ▴
Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PS1 N/ANot applicable: no amino acid change occurs (p.Tyr135=), so there is no altered residue to compare with a previously pathogenic variant. Details ▾Hide ▴
Reasoning

PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1 N/ANot applicable: no altered residue exists (synonymous change), so hot-spot or critical-domain membership cannot be evaluated. Details ▾Hide ▴
Reasoning

PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM4 N/ANot applicable: this synonymous variant causes no change in protein length. Details ▾Hide ▴
Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/ANot applicable: no missense change occurs at this residue, so there is nothing to compare with a known pathogenic missense. Details ▾Hide ▴
Reasoning

PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2 N/ANot applicable: no missense change is present, so the gene's missense-constraint properties are not relevant. Details ▾Hide ▴
Reasoning

PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP1 N/ANot applicable: no missense change is present, so the truncating-variant mechanism does not apply. Details ▾Hide ▴
Reasoning

BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3 N/ANot applicable: this synonymous variant causes no protein-length change within a repeat region. Details ▾Hide ▴
Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004655.4:c.405C>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Tyr135=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP7 N/ANot applicable: the no-splice-impact prediction was already counted under BP4, so BP7 would double-count it. Details ▾Hide ▴
Reasoning

The variant is synonymous, but its available computational prediction has already been used for BP4. Applying BP7 from the same no-splice-impact prediction would double-count computational evidence, so BP7 is not independently applied.

Rule
Do not double-count the same computational splice prediction across BP4 and BP7.
Evidence considered
  • The normalized consequence is synonymous, NP_004646.3:p.(Tyr135=).
  • SpliceAI max delta score is 0.00 and has been allocated to BP4; the same prediction is not reused for BP7.
Still missing
  • No independent evidence relevant to BP7 beyond the SpliceAI result is available in the case bundle.
Sources
spliceai ↗

Identifiers

Gene
AXIN2
Transcript
NM_004655.4
Coding (HGVS c.)
NM_004655.4:c.405C>T
Protein (HGVS p.)
NP_004646.3:p.(Tyr135=)
GRCh38
chr17:65558216 G>A
GRCh37
chr17:63554334 G>A
Location and type
Exon 2 · synonymous
ClinVar
464621

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…
gnomAD v4.1 116 / 1,613,976 alleles AF 7.19e-05 · 0 homozygotes · FAF 8.09e-05
gnomAD v2.1 4 / 251,492 alleles AF 1.59e-05 · 0 homozygotes · FAF 1.12e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 7.2e-05 · 116 / 1,613,976 alleles · 0 hom · FAF 8.1e-05
European (non-Finnish)113 / 1,180,024 9.6e-05
Remaining individuals3 / 62,486 4.8e-05
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 1.6e-05 · 4 / 251,492 alleles · 0 hom · FAF 1.1e-05
European (non-Finnish)4 / 113,766 3.5e-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= 7.18722e-05; MAF= 0.00719%, 116/1613976 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.57608e-05; MAF= 0.00958%, 113/1180024 alleles, homozygotes = 0); grpmax FAF= 8.092e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59051e-05; MAF= 0.00159%, 4/251492 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51599e-05; MAF= 0.00352%, 4/113766 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.002

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMet (supporting): SpliceAI max delta 0.00 is below the 0.10 benign threshold, indicating no splice impact. Details ▾Hide ▴
Reasoning

AXIN2 NM_004655.4:c.405C>T is synonymous (p.Tyr135=). In the absence of an AXIN2-specific specification, the generic non-missense SpliceAI path applies. SpliceAI max delta is 0.00, below the calibrated benign threshold (<0.10), supporting no splice impact; BP4 is met at supporting strength.

Rule
Generic non-missense PP3/BP4 splice-prediction fallback: SpliceAI max delta <0.10 supports BP4; do not combine splice and missense computational paths.
Evidence considered
  • No governing AXIN2 CSPEC, VCEP material, or gene-specific PP3/BP4 lookup was retrieved; generic ACMG/AMP fallback is therefore applicable.
  • SpliceAI Lookup reports no significant splice impact and max delta score 0.00 for NM_004655.4:c.405C>T. The generic fallback assigns non-missense variants to the SpliceAI path and defines BP4 at max delta <0.10.
  • Published computational-evidence calibration: PMID 36413997 supports use of SpliceAI <=0.10 for supporting benign computational evidence and >=0.20 for supporting pathogenic computational evidence; the observed score supports BP4.
Sources
spliceai ↗generic_acmg_combination_rules
PP3 Not met: SpliceAI max delta 0.00 vs the >0.20 pathogenic-evidence threshold. Details ▾Hide ▴
Reasoning

AXIN2 NM_004655.4:c.405C>T is synonymous (p.Tyr135=). With no AXIN2 VCEP specification available, the generic non-missense splice-prediction path applies. SpliceAI max delta is 0.00, below the pathogenic-evidence threshold (>0.20); PP3 is not met.

Rule
Generic non-missense PP3/BP4 splice-prediction fallback: SpliceAI max delta >0.20 supports PP3; do not combine splice and missense computational paths.
Evidence considered
  • No governing AXIN2 CSPEC, VCEP material, or gene-specific PP3/BP4 lookup was retrieved; generic ACMG/AMP fallback is therefore applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_004655.4:c.405C>T. The generic fallback assigns non-missense variants to the SpliceAI path and defines PP3 at max delta >0.20.
  • Published computational-evidence calibration: PMID 36413997 supports use of SpliceAI <=0.10 for supporting benign computational evidence and >=0.20 for supporting pathogenic computational evidence; the observed score does not support PP3.
Sources
spliceai ↗generic_acmg_combination_rules
BP7 N/ANot applicable: the no-splice-impact prediction was already counted under BP4, so BP7 would double-count it. Details ▾Hide ▴
Reasoning

The variant is synonymous, but its available computational prediction has already been used for BP4. Applying BP7 from the same no-splice-impact prediction would double-count computational evidence, so BP7 is not independently applied.

Rule
Do not double-count the same computational splice prediction across BP4 and BP7.
Evidence considered
  • The normalized consequence is synonymous, NP_004646.3:p.(Tyr135=).
  • SpliceAI max delta score is 0.00 and has been allocated to BP4; the same prediction is not reused for BP7.
Still missing
  • No independent evidence relevant to BP7 beyond the SpliceAI result is available in the case bundle.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    Karbassi I et al. · 2016
    The paper does not report the AXIN2 gene or the specific synonymous variant c.405C>T (NP_004646.3:p.(Y135=)). It describes a general rules-based variant pathogenicity scoring system applied to variants in 338 genes, using prediction tools, population frequency, co-occurrence, segregation, and functional-study data; no AXIN2-specific findings or observations for this variant are provided.
    Does not name this variant
    PMID 26467025 ↗
    Quoted passage
    Over 16,500 pathogenicity assessments on 11,894 distinct variants in 338 genes causing neurological, endocrine, and nephrotic genetic disorders were performed on the sequencing data.

    Materials and Methods, Data Collection and Storage

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    This paper is a general practice guideline for referral for cancer-predisposition assessment. It does not report the AXIN2 gene, the c.405C>T variant, the NP_004646.3:p.(Y135=) protein change, or any variant-specific functional, clinical, segregation, or population-frequency data relevant to this variant.
    Does not name this variant
    PMID 25394175 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 116 / 1,613,976 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 4 Likely benign · 1 Benign · 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

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= 7.18722e-05; MAF= 0.00719%, 116/1613976 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.57608e-05; MAF= 0.00958%, 113/1180024 alleles, homozygotes = 0); grpmax FAF= 8.092e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59051e-05; MAF= 0.00159%, 4/251492 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51599e-05; MAF= 0.00352%, 4/113766 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 464621)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.