Classification rationale

BP4 VUS

AXIN2 c.1059+8C>T unknown · exon 4i

VUS: BP4 (supporting) is met because SpliceAI maximum delta is 0.001, below the <=0.1 threshold.

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, supporting: SpliceAI maximum delta 0.001 is below the <=0.1 BP4 threshold.

SpliceAI reports DS_AG 0.000, DS_AL 0.001, DS_DG 0.001, and DS_DL 0.000 for NM_004655.4:c.1059+8C>T; the maximum delta is 0.001.The supplied generic SpliceAI calibration assigns BP4 supporting strength at max delta <=0.1, from Jaganathan et al. 2019, Cell (PMID:30661751).

spliceai ↗

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

Pathogenic

PVS1 Not met: noncanonical c.1059+8 intronic variant has no established protein consequence and SpliceAI max delta 0.001, so generic PVS1 is unsupported.

PS2 Not assessed: no parental testing or confirmed de novo occurrence is documented for NM_004655.4:c.1059+8C>T.

PS3 Not assessed: no variant-specific RNA, protein, cellular, or other validated functional assay result was reported for AXIN2 c.1059+8C>T.

PS4 Not assessed: no exact-variant case-control enrichment, affected-case count, odds ratio, or other prevalence metric is available.

PM2 Not met: the default gnomAD v4.1 overall allele frequency is 0.000270314, above the generic PM2 threshold of 0.0001.

PM3 Not assessed: no affected-proband observation or documented pathogenic variant in trans, phase, or recessive inheritance context is available.

PM6 Not assessed: no presumed de novo report, proband phenotype, or parental-testing context is documented for this variant.

PP1 Not assessed: zero informative familial meioses or affected-relative segregation observations are documented for this variant.

PP3 Not met: SpliceAI maximum delta 0.001 is below the >=0.2 supporting PP3 threshold.

PP4 Not assessed: no patient phenotype is documented to evaluate specificity for an AXIN2-related disorder.

PP5 Not met: exact-variant ClinVar record 136475 has 0 expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.

Benign

BA1 Not met: the highest default all-comers population allele frequency is 0.00770843, below the generic BA1 threshold of 0.05.

BS1 Not met: the highest default all-comers population allele frequency is 0.00770843, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD reports 3 homozygotes, but unaffected status and AXIN2 penetrance are not established for BS2.

BS3 Not assessed: no controlled variant-specific assay demonstrated normal or benign AXIN2 function for c.1059+8C>T.

BS4 Not assessed: no genotype-confirmed affected and unaffected relatives are available to demonstrate non-segregation.

BP2 Not assessed: no documented in-trans or in-cis pathogenic-variant co-occurrence, phase result, or applicable inheritance context is available.

BP5 Not assessed: no documented in-cis pathogenic variant or co-occurrence evidence is available for this exact variant.

BP6 Not met: exact-variant ClinVar record 136475 has 0 expert-panel submissions, so single-submitter Benign/Likely benign labels do not qualify for 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= 0.000270314; MAF= 0.02703%, 435/1609242 alleles, homozygotes = 3) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00770843; MAF= 0.77084%, 228/29578 alleles, homozygotes = 3); grpmax FAF= 0.00011388.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000318163; MAF= 0.03182%, 90/282874 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00617284; MAF= 0.61728%, 64/10368 alleles, homozygotes = 0); grpmax FAF= 8.806e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.000705677993703181, 13/18422 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.027% · 435 / 1,609,242
3 hom · FAF 0.011%

Ashkenazi Jewish 228 / 29,578	0.77% 3 hom
Remaining individuals 45 / 62,358	0.072%
European (non-Finnish) 154 / 1,175,562	0.013%
South Asian 6 / 90,996	0.0066%
Admixed American 2 / 60,012	0.0033%

+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, African/African American)

gnomAD v2.1

0.032% · 90 / 282,874
0 hom · FAF 0.0088%

Ashkenazi Jewish 64 / 10,368	0.62%
Remaining individuals 5 / 7,226	0.069%
European (non-Finnish) 17 / 129,176	0.013%
South Asian 3 / 30,616	0.0098%
Admixed American 1 / 35,440	0.0028%

+ 3 not observed (African/African American, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.071% · 13 / 18,422
0 hom · FAF 0.003%

Ashkenazi Jewish 11 / 832	1.3%
European (non-Finnish) 2 / 11,742	0.017%

+ 7 not observed (African/African American, Latino/Admixed American, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (6 clinical laboratories). (ClinVarID = 136475)

ClinVar ↗

In silico

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

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 · 4 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

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

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