Variant classification summary

NM_004655.4:c.1713-18G>A

AXIN2 · NP_004646.3:p.? · NM_004655.4

GRCh37: chr17:63533199 C>T · GRCh38: chr17:65537081 C>T

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

BP4 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.?

gnomAD AF

0.0015835149147193628 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: SpliceAI max delta 0.06 is below the <=0.1 threshold for a benign splice prediction.

2

VUS: BP4 alone does not satisfy a generic ACMG/AMP combination rule for a definitive classification.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion alone does not meet the Likely Benign or Benign thresholds, so the final call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	pvs1_generic_framework pvs1_variant_assessment spliceai PMID:25741868
PS1	N/A	Not applicable: c.1713-18G>A is intronic with protein consequence p.?, so no amino-acid substitution exists for PS1 comparison.	PMID:25741868
PS2	Not assessed	Not assessed: no proband de novo observation, parental genotypes, parentage confirmation, or phenotype documentation is available.
PS3	Not assessed	Not assessed: no validated AXIN2-specific functional assay demonstrates an abnormal effect for c.1713-18G>A.
PS4	Not assessed	Not assessed: no case-control counts, enrichment statistic, odds ratio, or validated PS4 threshold are available for this variant.
PM1	N/A	Not applicable: the intronic variant has protein consequence p.?, so it has no translated residue to assess against AXIN2 functional domains or hotspots.	PMID:25741868
PM2	Not met	Not met: gnomAD v4.1 overall allele frequency 0.00158351 exceeds the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic allele, phase, or definitive inheritance mode is documented for PM3.
PM4	N/A	Not applicable: this is an intronic single-nucleotide variant with protein consequence p.?, not an in-frame insertion or deletion.	pvs1_variant_assessment
PM5	N/A	Not applicable: c.1713-18G>A is intronic with p.? consequence, so PM5 has no amino-acid residue or missense change to compare.	PMID:25741868
PM6	Not assessed	Not assessed: no presumed de novo proband finding, parental absence result, parentage information, or phenotype documentation is available.
PP1	Not assessed	Not assessed: no affected relatives, carrier genotypes, phenotype assessments, pedigree, or informative meiosis count is available.
PP2	N/A	Not applicable: PP2 evaluates missense variation, whereas this variant is intronic and has predicted protein consequence p.?.	PMID:25741868
PP3	Not met	Not met: SpliceAI max delta 0.06 is below the 0.2 supporting PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or specific clinical diagnosis is available to evaluate phenotype specificity for AXIN2-related disease.
PP5	Not met	Not met: ClinVar variation 136485 has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum ancestry-specific frequency 0.00618132 is below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 maximum ancestry-specific frequency 0.00618132 is below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 8 homozygotes, but no phenotype or age data establish that these individuals were healthy adults.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated AXIN2-specific functional assay demonstrates a normal effect for c.1713-18G>A.
BS4	Not assessed	Not assessed: no family genotypes or phenotype data show that the variant fails to segregate with disease.
BP1	N/A	Not applicable: BP1 is restricted to missense variants, while this variant is intronic with predicted protein consequence p.?.	PMID:25741868
BP2	Not assessed	Not assessed: no pathogenic comparator allele or documented cis/trans phase is available, and the relevant inheritance mode is unresolved.
BP3	N/A	Not applicable: the variant is an intronic single-nucleotide change, not an in-frame coding indel in a repetitive region.	pvs1_variant_assessment
BP4	Met	Met at supporting strength: SpliceAI max delta 0.06 meets the <=0.1 BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no patient-level alternate molecular explanation is documented for a phenotype associated with this variant.
BP6	Not met	Not met: ClinVar variation 136485 has zero expert-panel submissions, so its laboratory Benign or Likely benign assertions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: NM_004655.4:c.1713-18G>A is intronic, whereas BP7 applies only to synonymous variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.