Classification rationale

BP4 VUS

AXIN2 c.1713-18G>A unknown · exon 6i

BP4 supporting: SpliceAI max delta 0.06 is below the <=0.1 threshold for a benign splice prediction. VUS: BP4 alone does not satisfy a generic ACMG/AMP combination rule for a definitive classification.

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 · 1 applied · 19 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting strength: SpliceAI max delta 0.06 meets the <=0.1 BP4 threshold.

NM_004655.4:c.1713-18G>A is an intronic variant; therefore SpliceAI is the sole applicable PP3/BP4 computational path.SpliceAI reports a maximum delta score of 0.06.The supplied generic SpliceAI calibration assigns BP4 supporting at <=0.1; the maximum delta score of 0.06 meets BP4.

spliceai ↗

Assessed · not applied · 7 not met · 12 not assessed

Pathogenic

PVS1 Not met: intronic c.1713-18G>A is outside canonical splice positions and has SpliceAI max delta 0.06, below the 0.2 splice-impact threshold.

PS2 Not assessed: no proband de novo observation, parental genotypes, parentage confirmation, or phenotype documentation is available.

PS3 Not assessed: no validated AXIN2-specific functional assay demonstrates an abnormal effect for c.1713-18G>A.

PS4 Not assessed: no case-control counts, enrichment statistic, odds ratio, or validated PS4 threshold are available for this variant.

PM2 Not met: gnomAD v4.1 overall allele frequency 0.00158351 exceeds the PM2 threshold of 0.0001.

PM3 Not assessed: no affected-proband observation, second pathogenic allele, phase, or definitive inheritance mode is documented for PM3.

PM6 Not assessed: no presumed de novo proband finding, parental absence result, parentage information, or phenotype documentation is available.

PP1 Not assessed: no affected relatives, carrier genotypes, phenotype assessments, pedigree, or informative meiosis count is available.

PP3 Not met: SpliceAI max delta 0.06 is below the 0.2 supporting PP3 threshold.

PP4 Not assessed: no patient phenotype or specific clinical diagnosis is available to evaluate phenotype specificity for AXIN2-related disease.

PP5 Not met: ClinVar variation 136485 has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.

Benign

BA1 Not met: gnomAD v4.1 maximum ancestry-specific frequency 0.00618132 is below the generic BA1 threshold of 0.05.

BS1 Not met: gnomAD v4.1 maximum ancestry-specific frequency 0.00618132 is below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD v4.1 reports 8 homozygotes, but no phenotype or age data establish that these individuals were healthy adults.

BS3 Not assessed: no validated AXIN2-specific functional assay demonstrates a normal effect for c.1713-18G>A.

BS4 Not assessed: no family genotypes or phenotype data show that the variant fails to segregate with disease.

BP2 Not assessed: no pathogenic comparator allele or documented cis/trans phase is available, and the relevant inheritance mode is unresolved.

BP5 Not assessed: no patient-level alternate molecular explanation is documented for a phenotype associated with this variant.

BP6 Not met: ClinVar variation 136485 has zero expert-panel submissions, so its laboratory Benign or Likely benign assertions cannot trigger BP6.

N/A · 8 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= 0.00158351; MAF= 0.15835%, 2529/1597080 alleles, homozygotes = 8) and has highest observed frequency in the Middle Eastern population (AF= 0.00618132; MAF= 0.61813%, 36/5824 alleles, homozygotes = 1); grpmax FAF= 0.00458929.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00155232; MAF= 0.15523%, 394/253814 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.0028228; MAF= 0.28228%, 93/32946 alleles, homozygotes = 1); grpmax FAF= 0.00233546.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0014116625040721034, 26/18418 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.16% · 2529 / 1,597,080
8 hom · FAF 0.46%

Middle Eastern 36 / 5,824	0.62% 1 hom
Amish 4 / 912	0.44%
Admixed American 219 / 58,362	0.38% 2 hom
Remaining individuals 131 / 62,216	0.21% 2 hom
European (non-Finnish) 1955 / 1,177,112	0.17% 1 hom
Ashkenazi Jewish 32 / 29,354	0.11%
South Asian 98 / 90,458	0.11% 2 hom
African/African American 49 / 75,016	0.065%
European (Finnish) 5 / 53,086	0.0094%

+ 1 not observed (East Asian)

gnomAD v2.1

0.16% · 394 / 253,814
2 hom · FAF 0.23%

Admixed American 93 / 32,946	0.28% 1 hom
Remaining individuals 18 / 6,784	0.27%
European (non-Finnish) 213 / 116,210	0.18%
South Asian 40 / 29,616	0.14% 1 hom
Ashkenazi Jewish 13 / 9,856	0.13%
African/African American 16 / 23,066	0.069%
European (Finnish) 1 / 16,730	0.006%

+ 1 not observed (East Asian)

gnomAD Canada 🇨🇦

0.14% · 26 / 18,418
0 hom · FAF 0.092%

Middle Eastern 1 / 144	0.69%
Remaining individuals 6 / 1,138	0.53%
European (non-Finnish) 17 / 11,738	0.14%
Ashkenazi Jewish 1 / 832	0.12%
Latino/Admixed American 1 / 838	0.12%

+ 4 not observed (African/African American, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (4 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 136485)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 2 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

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

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