Variant classification summary

NM_004655.4:c.1059+8C>T

AXIN2 · NP_004646.3:p.? · NM_004655.4

GRCh37: chr17:63537565 G>A · GRCh38: chr17:65541447 G>A

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

0.0002703136010618664 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting benign criterion alone does not meet the thresholds for Benign or Likely Benign, so the final classification 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: noncanonical c.1059+8 intronic variant has no established protein consequence and SpliceAI max delta 0.001, so generic PVS1 is unsupported.	pvs1_generic_framework spliceai PMID:25741868
PS1	N/A	Not applicable: c.1059+8C>T is intronic with predicted protein consequence p.?, so no amino-acid change exists for PS1 comparison.	spliceai
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo occurrence is documented for NM_004655.4:c.1059+8C>T.
PS3	Not assessed	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	Not assessed: no exact-variant case-control enrichment, affected-case count, odds ratio, or other prevalence metric is available.	PMID:25394175
PM1	N/A	Not applicable: the intronic variant has predicted protein consequence p.?, so it cannot be mapped to a missense functional domain or residue hotspot.	spliceai
PM2	Not met	Not met: the default gnomAD v4.1 overall allele frequency is 0.000270314, above the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation or documented pathogenic variant in trans, phase, or recessive inheritance context is available.
PM4	N/A	Not applicable: c.1059+8C>T is intronic with protein consequence p.?, not an established in-frame coding length change.	pvs1_variant_assessment
PM5	N/A	Not applicable: c.1059+8C>T is intronic with protein consequence p.?, so PM5's same-residue missense comparison cannot be performed.
PM6	Not assessed	Not assessed: no presumed de novo report, proband phenotype, or parental-testing context is documented for this variant.
PP1	Not assessed	Not assessed: zero informative familial meioses or affected-relative segregation observations are documented for this variant.
PP2	N/A	Not applicable: the variant is intronic with predicted protein consequence p.?, whereas PP2 is restricted to missense variants.
PP3	Not met	Not met: SpliceAI maximum delta 0.001 is below the >=0.2 supporting PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype is documented to evaluate specificity for an AXIN2-related disorder.
PP5	Not met	Not met: exact-variant ClinVar record 136475 has 0 expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest default all-comers population allele frequency is 0.00770843, below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest default all-comers population allele frequency is 0.00770843, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 3 homozygotes, but unaffected status and AXIN2 penetrance are not established for BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no controlled variant-specific assay demonstrated normal or benign AXIN2 function for c.1059+8C>T.
BS4	Not assessed	Not assessed: no genotype-confirmed affected and unaffected relatives are available to demonstrate non-segregation.
BP1	N/A	Not applicable: c.1059+8C>T is intronic with predicted protein consequence p.?, not a missense variant required for BP1.
BP2	Not assessed	Not assessed: no documented in-trans or in-cis pathogenic-variant co-occurrence, phase result, or applicable inheritance context is available.
BP3	N/A	Not applicable: the variant is a noncanonical intronic SNV, not an in-frame deletion or insertion in a repetitive protein region.	pvs1_variant_assessment
BP4	Met	Met, supporting: SpliceAI maximum delta 0.001 is below the <=0.1 BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no documented in-cis pathogenic variant or co-occurrence evidence is available for this exact variant.
BP6	Not met	Not met: exact-variant ClinVar record 136475 has 0 expert-panel submissions, so single-submitter Benign/Likely benign labels do not qualify for BP6.	clinvar
BP7	N/A	Not applicable: the variant is an intronic splice-region change, not a synonymous variant.

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.