Classification rationale

BA1BP3BP4 Benign

AXIN2 c.2013_2024del in_frame_indel_unknown · exon 8

BA1 (stand-alone benign): gnomAD v4.1 African/African American allele frequency 7.33% exceeds the 5% BA1 threshold. BP3 (supporting): in-frame 12-nucleotide deletion falls in a repetitive 6-G homopolymer region without known function, outside all conserved domains. BP4 (supporting): SpliceAI max delta 0.019 predicts no splice-altering impact (threshold ~0.2). Overall classification: Benign, per generic ACMG/AMP 2015 fallback combination rules driven by BA1 at stand-alone strength.

BA1 + BP3 + BP4 → Benign

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

AXIN2 NM_004655.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 18 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 · 3

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

Met (stand-alone benign): gnomAD v4.1 African/African American allele frequency 7.33% exceeds the 5% BA1 threshold.

No AXIN2 ClinGen VCEP specification or local gene-specific framework was available; generic ACMG/AMP was therefore used.gnomAD v4.1 reports 220 African/African American homozygotes, and gnomAD v2.1 reports 66, supporting that the high ancestry-specific frequency is a reproducible population observation rather than a single-dataset artifact.The BA1 threshold used is from Richards et al. (PMID:25741868): allele frequency above 5% in a population reference dataset is benign stand-alone evidence.

gnomad_v4 ↗gnomad_v2 ↗PMID:25741868 ↗

✓

BP3 supporting Benign

Met (supporting): in-frame 12-nucleotide deletion in a repetitive 6-G homopolymer region outside all known functional domains.

Richards et al. 2015 (PMID:25741868) Table 3 defines BP3 as in-frame deletions/insertions in a repeat region without a known function; the companion PM4 passage retrieved in full text (publications/25741868.txt) confirms the in-frame deletion/insertion framework, though the BP3 sentence itself lies beyond the 40KB truncation of the retrieved text.Consequence: Mutalyzer/VariantValidator (prefetch.json) confirm a 12-nt in-frame deletion, NP_004646.3:p.(Thr672_Arg675del), entirely within exon 8 (VariantValidator start_exon/end_exon = 8; Mutalyzer exon 8 = c.1908-2141) of the MANE Select transcript NM_004655.4; no frameshift, so no NMD is expected.Repeat-region context: the deleted interval ACGGGGGGTGGTG contains a 6-G homopolymer run, and Mutalyzer normalization reports shift 6, indicating the deletion boundaries are ambiguous within a repetitive sequence.

PMID:25741868 ↗spliceai ↗gnomad_v4 ↗gnomad_v2 ↗clinvar ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.019, well below the ~0.2 threshold for splice-altering impact.

SpliceAI direct query for NM_004655.4:c.2013_2024del returned max_delta_score=0.019 (DS_AG=0.002, DS_AL=0.013, DS_DG=0.019, DS_DL=0.011), evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).'SpliceAI's ~0.2 delta-score threshold for high-precision splice-altering prediction comes from Jaganathan KK et al., 'Predicting Splicing from Primary Sequence with Deep Learning,' Cell 2019, PMID 30661751.The variant is a 12-bp in-frame deletion (p.Thr672_Arg675del), not a missense or synonymous substitution, so REVEL/BayesDel/aGVGD missense predictors and BP7 do not apply.

spliceai ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PS2 Not assessed: no proband phenotype or parental genotype data were available to evaluate a confirmed de novo occurrence.

PS3 Not assessed: no validated functional assay data addressing this variant were available.

PS4 Not assessed: no variant-specific case-control or cohort enrichment data were provided.

PM2 Not met: gnomAD v4.1 African/African American allele frequency is 7.33%, far above rarity thresholds for PM2.

PM3 Not assessed: no proband observation or phase result establishes this variant in trans with a pathogenic allele.

PM4 Not met: the in-frame deletion lies in a repetitive 6-G homopolymer region, which PM4 explicitly excludes.

PM6 Not assessed: no parental genotype data were available to evaluate an assumed de novo occurrence.

PP1 Not assessed: no genotyped relatives or informative meioses were provided, so co-segregation could not be evaluated.

PP3 Not met: SpliceAI max delta 0.019, far below the ~0.2 threshold for predicted splice-altering impact.

PP4 Not assessed: no phenotype-to-gene specificity evidence was provided for the tested individual.

PP5 Not met: the ClinVar record carries no pathogenic or likely pathogenic expert-panel assertion.

Benign

BS1 Not met: BA1 already applies at stand-alone strength, superseding the lower-strength BS1 frequency criterion.

BS2 Not assessed: homozygotes are reported, but individual phenotypes, ages, and disease status are not documented.

BS3 Not assessed: no benign-consistent functional assay result for this variant was available.

BS4 Not assessed: no informative family phenotypes and genotypes were provided to establish lack of segregation.

BP2 Not assessed: no second AXIN2 variant or phase result was provided to evaluate cis/trans configuration.

BP5 Not assessed: no evidence that an alternate molecular diagnosis fully explains the phenotype was provided.

BP6 Not met: the ClinVar record carries no benign or likely benign expert-panel assertion.

N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00393451; MAF= 0.39345%, 6349/1613670 alleles, homozygotes = 229) and has highest observed frequency in the African/African American population (AF= 0.0733307; MAF= 7.33307%, 5502/75030 alleles, homozygotes = 220); grpmax FAF= 0.0717121.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00718265; MAF= 0.71826%, 1983/276082 alleles, homozygotes = 66) and has highest observed frequency in the African/African American population (AF= 0.0737246; MAF= 7.37246%, 1789/24266 alleles, homozygotes = 66); grpmax FAF= 0.0717742.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.004562242016076472, 84/18412 alleles, homozygotes = 3).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.39% · 6349 / 1,613,670
229 hom · FAF 7.2%

African/African American 5502 / 75,030	7.3% 220 hom
Middle Eastern 39 / 6,062	0.64% 1 hom
Remaining individuals 342 / 62,500	0.55% 7 hom
Admixed American 267 / 60,012	0.44%
South Asian 23 / 91,054	0.025% 1 hom
European (non-Finnish) 174 / 1,179,970	0.015%
East Asian 2 / 44,878	0.0045%

+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.72% · 1983 / 276,082
66 hom · FAF 7.2%

African/African American 1789 / 24,266	7.4% 66 hom
Remaining individuals 26 / 7,088	0.37%
Admixed American 128 / 35,304	0.36%
European (non-Finnish) 34 / 123,828	0.027%
South Asian 5 / 30,518	0.016%
East Asian 1 / 19,858	0.005%

+ 2 not observed (Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

0.46% · 84 / 18,412
3 hom · FAF 5.3%

indel · split

African/African American 67 / 1,018	6.6% 3 hom
Latino/Admixed American 6 / 838	0.72%
Remaining individuals 7 / 1,134	0.62%
European (non-Finnish) 4 / 11,738	0.034%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (14 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 182018)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AXIN2, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61057671, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

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