Classification rationale

PM2 BP4 VUS

AXIN2 c.405C>T synonymous · exon 2

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.00719% with zero homozygotes. BP4 (Supporting): SpliceAI max delta 0.00, below the 0.10 benign threshold, indicating no splice impact. Final: VUS - the supporting pathogenic PM2 and supporting benign BP4 offset each other under the generic ACMG/AMP 2015 rule, meeting no classification threshold.

PM2 + BP4 → VUS

Gene diagram · NM_004655.4 · variants mapped to exon structure

AXIN2 NM_004655.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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

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.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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

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.

spliceai ↗

Assessed · not applied · 5 not met · 12 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence with confirmed parentage was documented.

PS3 Not assessed: no functional assay demonstrating a disease-relevant effect of this variant was available.

PS4 Not assessed: no affected-case series or case-control data for this variant were provided.

PM3 Not assessed: no second pathogenic variant in trans or other inheritance data were documented.

PM6 Not assessed: no suspected de novo occurrence with parental testing was reported.

PP1 Not assessed: no family segregation or co-segregation analysis was documented.

PP3 Not met: SpliceAI max delta 0.00 vs the >0.20 pathogenic-evidence threshold.

PP4 Not assessed: no individual-level phenotype or diagnostic workup was provided.

PP5 Not met: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this exact variant.

Benign

BA1 Not met: highest population frequency 0.00958% (gnomAD v4.1) is far below a stand-alone benign threshold.

BS1 Not met: allele frequency 0.00719% does not exceed expected levels for a rare AXIN2-associated disorder.

BS2 Not assessed: no phenotype-verified healthy adult carriers were documented.

BS3 Not assessed: no functional assay evidence of no damaging effect was available.

BS4 Not assessed: no tested unaffected carriers or non-segregation data were documented.

BP2 Not assessed: no phase information or co-occurrence with a pathogenic variant was documented.

BP5 Not assessed: no alternate molecular diagnosis was documented in the variant carrier.

BP6 Not met: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant.

N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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.

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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0072% · 116 / 1,613,976
0 hom · FAF 0.0081%

European (non-Finnish) 113 / 1,180,024	0.0096%
Remaining individuals 3 / 62,486	0.0048%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0016% · 4 / 251,492
0 hom · FAF 0.0011%

European (non-Finnish)

4 / 113,766

0.0035%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

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)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

25394175 ↗ 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. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR