Variant classification summary

NM_004655.4:c.405C>T

AXIN2 · NP_004646.3:p.(Tyr135=) · NM_004655.4

GRCh37: chr17:63554334 G>A · GRCh38: chr17:65558216 G>A

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Tyr135=)

gnomAD AF

7.187219636475388e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.00719% with zero homozygotes.

2

BP4 (Supporting): SpliceAI max delta 0.00, below the 0.10 benign threshold, indicating no splice impact.

3

Final: VUS - the supporting pathogenic PM2 and supporting benign BP4 offset each other under the generic ACMG/AMP 2015 rule, meeting no classification threshold.

Final determination: Generic ACMG/AMP 2015 fallback rules classify all combinations not meeting a pathogenic, likely pathogenic, benign, or likely benign threshold, including conflicting PM2 supporting plus BP4 supporting evidence, as 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	N/A	Not applicable: this synonymous variant produces no null allele, so no nonsense-mediated decay or loss-of-function mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid change occurs (p.Tyr135=), so there is no altered residue to compare with a previously pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parentage was documented.
PS3	Not assessed	Not assessed: no functional assay demonstrating a disease-relevant effect of this variant was available.
PS4	Not assessed	Not assessed: no affected-case series or case-control data for this variant were provided.
PM1	N/A	Not applicable: no altered residue exists (synonymous change), so hot-spot or critical-domain membership cannot be evaluated.	generic_acmg_combination_rules
PM2	Met	Met (supporting): extremely rare in gnomAD v4.1 at 0.00719% allele frequency (116/1,613,976 alleles) with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no second pathogenic variant in trans or other inheritance data were documented.
PM4	N/A	Not applicable: this synonymous variant causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change occurs at this residue, so there is nothing to compare with a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no suspected de novo occurrence with parental testing was reported.
PP1	Not assessed	Not assessed: no family segregation or co-segregation analysis was documented.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are not relevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 vs the >0.20 pathogenic-evidence threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no individual-level phenotype or diagnostic workup was provided.
PP5	Not met	Not met: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: highest population frequency 0.00958% (gnomAD v4.1) is far below a stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency 0.00719% does not exceed expected levels for a rare AXIN2-associated disorder.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no phenotype-verified healthy adult carriers were documented.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay evidence of no damaging effect was available.
BS4	Not assessed	Not assessed: no tested unaffected carriers or non-segregation data were documented.
BP1	N/A	Not applicable: no missense change is present, so the truncating-variant mechanism does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase information or co-occurrence with a pathogenic variant was documented.
BP3	N/A	Not applicable: this synonymous variant causes no protein-length change within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.00 is below the 0.10 benign threshold, indicating no splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis was documented in the variant carrier.
BP6	Not met	Not met: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: the no-splice-impact prediction was already counted under BP4, so BP7 would double-count it.	spliceai

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