Classification rationale

PM2 BP4 VUS

AXIN2 c.1365A>T synonymous · exon 6

VUS: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1 (0 of 1,559,354 alleles). VUS: BP4 supporting is met because the synonymous change has a SpliceAI maximum delta of 0.001, below the 0.1 no-impact cutoff. VUS: no pathogenic criterion is met and the only benign criterion met is BP4 supporting, so no combination rule for Benign, Likely Benign, Likely Pathogenic or Pathogenic is reached.

PM2 + BP4 → VUS

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.

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 at supporting: variant is absent from gnomAD v4.1 (0/1,559,354 alleles), below the 0.0001 PM2 threshold.

gnomAD v4.1 (v4.1.0, GRCh38 chr17-65537671-T-A): total AC=0/AN=1,559,354 (AF=0.000000), homozygotes=0; exome AC=0/AN=1,407,484; genome AC=0 with genome AN=0 in the fetched figures; every ancestry group AF=0 (European non-Finnish AN=1,153,178; African/African American AN=73,968; South Asian AN=86,292; Admixed American AN=51,594).gnomAD v2.1 (GRCh37 17-63533789-T-A, exomes): absent, search_status absent with no errors recorded.gnomAD v2.1 non-cancer (exomes-only figures) absent and gnomAD v3.1 non-cancer (genomes-only) absent; neither subset is a standalone source_registry key, so they are documented here instead of being cited in evidence_refs.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP4 supporting Benign

Met at supporting strength: SpliceAI max delta 0.001 is at or below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.

Consequence type fixed first: NM_004655.4:c.1365A>T / NP_004646.3:p.(Pro455=) is synonymous, so BP4 is assessed on the SpliceAI splice path only; the REVEL missense path does not apply (REVEL not found for this variant) and BayesDel has no generic ACMG-strength calibration.SpliceAI Lookup for NM_004655.4:c.1365A>T / 17-63533789-T-A: max delta score 0.001 (DS_AG 0.000, DS_AL 0.001, DS_DG 0.001, DS_DL 0.000), DP_AG 104, DP_AL 75, DP_DG 482, DP_DL -418; Pangolin SG 0.002, SL -0.001.Threshold applied verbatim from the supplied generic ACMG/ClinGen-SVI calibration: SpliceAI max delta <= 0.1 -> BP4 (supporting) (Jaganathan et al. 2019, Cell; PMID:30661751). 0.001 satisfies it.

spliceai ↗

Assessed · not applied · 11 not met · 6 not assessed

Pathogenic

PS2 Not assessed: no proband phenotype and zero parental genotypes in the case, so a confirmed de novo occurrence can be neither shown nor excluded.

PS3 Not met: no functional assay of AXIN2 c.1365A>T (p.Pro455=) exists in any consulted source, so damaging-effect evidence is absent.

PS4 Not met: no case-control or affected-cohort enrichment data exists for this variant, which is absent from gnomAD v4.1 (0/1,559,354 alleles).

PM6 Not assessed: no proband phenotype and no parental testing status is recorded, so an assumed de novo occurrence cannot be evaluated.

PP1 Not assessed: zero pedigrees and zero genotyped relatives are available, so co-segregation and its informative meiosis count cannot be evaluated.

PP3 Not met: SpliceAI max delta 0.001 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, which is scored on the splice path only.

PP4 Not assessed: no proband phenotype or family history was available to test specificity for a single-gene AXIN2 phenotype.

PP5 Not met: ClinVar has four exact-variant submissions, none from an expert panel, with only a 2-star aggregate label.

Benign

BA1 Not met: gnomAD v4.1 allele frequency is 0 (0/1,559,354 alleles), far below the 0.05 stand-alone benign threshold.

BS1 Not met: gnomAD v4.1 allele frequency is 0 (0/1,559,354 alleles), far below the 0.01 strong benign threshold.

BS2 Not met: gnomAD v4.1 homozygote count is 0 and allele count is 0/1,559,354, so no healthy-adult carrier was observed.

BS3 Not met: no functional assay of AXIN2 c.1365A>T exists; SpliceAI max delta 0.001 is computational, not assay evidence of normal function.

BS4 Not assessed: no affected relatives are genotyped, so non-segregation cannot be demonstrated; ClinVar's benign assertions are not family-level evidence.

BP2 Not met: neither the four ClinVar submissions nor the case literature report c.1365A>T in cis or in trans with a pathogenic variant.

BP5 Not assessed: no proband-level molecular data was available to identify an alternate molecular basis for disease.

BP6 Not met: no expert-panel classification exists for this exact variant; all four ClinVar submissions are ordinary clinical laboratories (2 stars).

BP7 Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.001, is already credited under BP4, and no conservation data is available.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1559354 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73968 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,559,354
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 1128484)

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 · 2 PMIDs not cited in assessment

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

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