Classification rationale

BP4 VUS

AXIN2 c.2433G>A synonymous · exon 11

BP4 supporting: SpliceAI max delta 0.003 predicts no splice impact for this synonymous AXIN2 variant.

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 0.003 is below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.

Consequence type fixed first: NM_004655.4:c.2433G>A / NP_004646.3:p.(Glu811=) 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 and no VCEP-supplied AXIN2 cutoff.SpliceAI Lookup for NM_004655.4:c.2433G>A / 17-63526193-C-T: maximum delta score 0.003 (DS_AG 0.000, DS_AL 0.000, DS_DG 0.003, DS_DL 0.000), DP_AG 6, DP_AL 483, DP_DG 396, DP_DL 101; Pangolin SG 0.002, SL -0.002; spliceai_available = true.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, cited here in prose because it is not a source_registry key for this case). 0.003 satisfies it.

spliceai ↗PMID:25741868 ↗

Assessed · not applied · 11 not met · 8 not assessed

Pathogenic

PS2 Not assessed: no parental-tested proband or de novo report in any of 12 ClinVar submissions for AXIN2 c.2433G>A.

PS3 Not met: no functional assay of AXIN2 c.2433G>A exists in the record, and SpliceAI max delta 0.003 is in-silico, not a validated assay.

PS4 Not met: no cohort or case-control enrichment data report c.2433G>A in affected individuals, and the generic ACMG PS4 rule sets no numeric threshold.

PM2 Not met: gnomAD v4.1 total allele frequency 1.23e-4 and grpmax filtering frequency 1.35e-4 both exceed the 1e-4 PM2 threshold.

PM3 Not assessed: no proband genotype, second allele, or phase determination exists, and AXIN2 disease is dominant rather than recessive.

PM6 Not assessed: no proband or parental samples reported, so an assumed-but-unconfirmed de novo event cannot be evaluated for this variant.

PP1 Not assessed: no pedigree or genotyped relatives; zero segregation evidence for AXIN2 c.2433G>A among 12 ClinVar submissions and the papers reviewed.

PP3 Not met: SpliceAI max delta 0.003 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, scored on the splice path only.

PP4 Not assessed: no proband phenotype or HPO data were provided for this case, so phenotype specificity could not be evaluated.

PP5 Not met: the exact variant has no ClinVar expert-panel submission (0 of 12 audited submissions), so the expert-panel gate for PP5 is unmet.

Benign

BA1 Not met: the highest observed allele frequency is 1.94e-4 (European non-Finnish, gnomAD v2.1), over two orders of magnitude below the 0.05 BA1 threshold.

BS1 Not met: the highest observed allele frequency, 1.94e-4 (European non-Finnish, gnomAD v2.1), is roughly 50-fold below the 0.01 BS1 threshold.

BS2 Not met: zero homozygotes in gnomAD v2.1/v4.1, and AXIN2 disease is adult-onset with incomplete penetrance, so healthy-adult observations do not satisfy BS2.

BS3 Not met: no functional study of AXIN2 c.2433G>A showed normal function or splicing; benign ClinVar status and SpliceAI 0.003 are not assay evidence.

BS4 Not assessed: no affected-relative genotypes reported, so lack of segregation cannot be shown from the 12 ClinVar submissions or the papers reviewed.

BP2 Not assessed: no second variant, proband genotype, or cis/trans phase result exists, so no allelic configuration with a pathogenic variant is established.

BP5 Not assessed: no case-level data on an alternate molecular basis for disease were available for this individual.

BP6 Not met: no ClinVar expert panel has submitted on this exact variant (0 of 12 audited submissions); ordinary laboratory Benign/Likely benign labels cannot trigger BP6.

BP7 Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.003, is already credited under BP4, and no conservation data is available.

N/A · 8 PVS1 · PS1 · PM1 · 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= 0.000123279; MAF= 0.01233%, 199/1614228 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000153384; MAF= 0.01534%, 181/1180046 alleles, homozygotes = 0); grpmax FAF= 0.00013499.

v2.1

This variant is present in gnomAD v2.1 (AF= 9.90239e-05; MAF= 0.00990%, 28/282760 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000193699; MAF= 0.01937%, 25/129066 alleles, homozygotes = 0); grpmax FAF= 0.00014552.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.012% · 199 / 1,614,228
0 hom · FAF 0.013%

European (non-Finnish) 181 / 1,180,046	0.015%
Remaining individuals 8 / 62,510	0.013%
Admixed American 5 / 60,026	0.0083%
African/African American 3 / 75,054	0.004%
East Asian 1 / 44,892	0.0022%
European (Finnish) 1 / 64,032	0.0016%

+ 4 not observed (Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0099% · 28 / 282,760
0 hom · FAF 0.015%

European (non-Finnish) 25 / 129,066	0.019%
Admixed American 2 / 35,440	0.0056%
African/African American 1 / 24,964	0.004%

+ 5 not observed (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 (9 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 182020)

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 ↗

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

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