Variant classification summary

NM_004655.4:c.432T>C

AXIN2 · NP_004646.3:p.(Ile144=) · NM_004655.4

GRCh37: chr17:63554307 A>G · GRCh38: chr17:65558189 A>G

Gene: AXIN2 Transcript: NM_004655.4

Final call

Benign

BA1 stand-alone benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Ile144=)

gnomAD AF

0.02013883983726841 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004655.4:c.432T>C (p.Ile144=) is a synonymous variant in AXIN2. This variant is present at extremely high frequency in population databases: gnomAD v2.1 overall allele frequency is 4.39% (12,423/282,858 alleles) with 675 homozygotes, and the East Asian subpopulation frequency is 16.63% (3,319/19,952 alleles) with 290 homozygotes. gnomAD v4.1 corroborates with overall AF=2.01% (32,503/1,613,946 alleles, 1,500 homozygotes) and East Asian AF=16.48%. The grpmax filtering allele frequency is 16.2%, far exceeding the 1% BA1 stand-alone benign threshold.

2

SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), consistent with a synonymous change that does not alter the amino acid sequence (p.Ile144=) and does not create or disrupt splice sites.

3

This variant has been classified as Benign in ClinVar (VariationID 259515) by 15 clinical laboratories with criteria provided. While the review status is single submitter (1-star), the unanimous benign classification across multiple submitters is consistent with the population frequency and in silico evidence.

4

Overall classification: Benign. BA1 (stand-alone benign) is met based on allele frequency far exceeding 1%. One stand-alone benign criterion is sufficient for a Benign classification per ACMG/AMP 2015 combination rules. Additional supporting benign criteria BP4 and BP7 further reinforce the benign classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Synonymous variant (NP_004646.3:p.(Ile144=)); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable.	pvs1_variant_assessment
PS1	N/A	Synonymous variant produces no amino acid change (p.Ile144=); no comparator pathogenic missense change at this position exists.
PS2	Not met	No de novo confirmation data available for this variant.
PS3	Not met	No variant-specific functional studies identified for this synonymous variant (p.Ile144=). No experimental data demonstrating a damaging functional effect exist.
PS4	N/A	Variant is present at high population frequency (AF=4.39% gnomAD v2.1, 16.63% East Asian, 675 homozygotes), inconsistent with pathogenicity. Prevalence comparison in affected vs. controls is not meaningful.	gnomad_v2
PS5	N/A	Synonymous variant produces no amino acid change (p.Ile144=); no different amino acid change at the same codon can exist for comparison.
PM1	N/A	Synonymous variant (p.Ile144=) does not alter the amino acid sequence; even if located within a critical functional domain, no domain disruption occurs.
PM2	Not met	Variant is common in population databases. gnomAD v2.1 AF=4.39% (12,423/282,858 alleles, 675 homozygotes), far exceeding the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant produces no amino acid change (p.Ile144=); no comparator missense variant at this residue exists. PM5 candidate harvesting confirmed not applicable.	pm5_candidates
PM6	Not met	No de novo confirmation data available for this variant.
PP1	Not met	No co-segregation data available for this variant.
PP2	N/A	Synonymous variant, not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	Multiple in silico tools predict no impact. SpliceAI max delta score is 0.00 (no splice effect). REVEL and BayesDel not available for this synonymous variant. No computational evidence supports pathogenicity.	spliceai
PP4	Not met	No patient phenotype or family history data available for assessment.
PP5	Not met	ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), not Pathogenic. Review status is criteria provided, single submitter (1-star), which does not meet the 3-star expert panel threshold required for automatic PP5 application.	clinvar
BA1	Met	Variant allele frequency far exceeds the BA1 threshold of 1%. gnomAD v2.1: AF=4.39% (12,423/282,858 alleles, 675 homozygotes); highest population frequency is East Asian at 16.63% (3,319/19,952 alleles, 290 homozygotes); grpmax FAF=16.20%. gnomAD v4.1: AF=2.01% (32,503/1,613,946 alleles, 1,500 homozygotes); East Asian AF=16.48%; grpmax FAF=16.16%.	gnomad_v2 gnomad_v4
BS1	Not assessed	Superseded by BA1 (stand-alone benign). Variant frequency exceeds both BS1 (>0.3%) and BA1 (>1%) thresholds; BA1 provides the stronger level of evidence.
BS2	Not met	Although 675 homozygotes in gnomAD v2.1 suggest observation in healthy individuals, no phenotype-confirmed healthy adult data with full penetrance expectation is available. Population frequency alone is captured under BA1.
BS3	Not met	No functional studies demonstrating no damaging effect are available for this synonymous variant.
BS4	Not met	No segregation data available for assessment of lack of co-segregation with disease.
BP1	N/A	Synonymous variant, not a missense change. BP1 applies only to missense variants in genes where a truncating mechanism is the primary cause of disease.
BP2	Not met	No data available on observation in trans with a pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no impact. SpliceAI predicts no splicing effect (max delta=0.00). REVEL and BayesDel are not scored for synonymous variants but the absence of any predicted effect across available tools is consistent with a benign impact.	spliceai
BP5	Not met	No evidence that this variant was found in a case with an alternate molecular basis for disease. COSMIC reports 32 somatic observations (COSV61056425) but this does not satisfy BP5 requirements.
BP6	Not met	ClinVar classification is Benign (VariationID 259515, 15 clinical laboratories), but the review status is criteria provided, single submitter (1-star). BP6 automatic application requires 3-star expert panel status. This does not qualify.	clinvar
BP7	Met	Synonymous variant (NP_004646.3:p.(Ile144=)) with no predicted splice impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences and no cryptic splice site creation. The nucleotide position shows high population variation (AF=4.39%), consistent with low evolutionary constraint.	spliceai gnomad_v2

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