NM_004655.4:c.1235A>G

AXIN2 · NP_004646.3:p.(Asn412Ser) · NM_004655.4

GRCh37: chr17:63533919 T>C · GRCh38: chr17:65537801 T>C

Gene: AXIN2 Transcript: NM_004655.4

Final call

Likely Benign

BS1 strong BP1 supporting BP4 moderate

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Asn412Ser)

gnomAD AF

0.007933206785198406 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Likely Benign: BS1 (strong) — ancestry-specific filtering frequency 4.11% in South Asians is above the 1% benign threshold.

BP1 (supporting) — this missense change does not fit AXIN2's truncating disease mechanism.

BP4 (moderate) — REVEL 0.119 predicts a tolerated amino-acid substitution.

No pathogenic criterion met — all 15 pathogenic-direction criteria are not met, not applicable, or unassessed.

Final determination: Under the generic ACMG/AMP 2015 rules, one strong benign criterion (BS1) plus one supporting benign criterion (BP1), with BP4 additionally met at moderate strength, yields Likely Benign.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004655.4:c.1235A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Asn412Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the same amino-acid change p.Asn412Ser is an established Benign/Likely benign allele in ClinVar, not a previously established pathogenic variant.	clinvar PMID:16941501 PMID:21476993 PMID:25741868
PS2	Not assessed	Not assessed: the sole reported carrier had no family history, but zero parental genotypes were reported, so confirmed de novo status is undetermined.	PMID:16941501 PMID:21476993 PMID:25741868
PS3	Not met	Not met: no assay shows a damaging effect; the only exact-variant experiment found no splicing alteration.	PMID:16941501 PMID:21476993 PMID:25741868
PS4	Not met	Not met: the variant showed no significant case-control enrichment (1/25 cases vs 4/275 controls, OR ~2.8, Fisher p=0.355; p<=0.05? no).	PMID:21476993 PMID:16941501 PMID:25741868 gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1	Not met	Not met: residue 412 lies outside AXIN2's RGS (81-200) and DIX (761-843) domains, is not a hot spot, and gnomAD v4.1 0.79% with 165 homozygotes shows benign variation there.	clinvar gnomad_v2 gnomad_v4 PMID:16941501 PMID:25741868
PM2	Not met	Not met: allele frequency 0.79% (gnomAD v4.1) is about 79-fold above the 0.0001 PM2 supporting threshold, with 165 homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not met	Not met: no pathogenic AXIN2 variant in trans with c.1235A>G has been reported, and its only co-inherited allele (c.1530G>A) is a non-pathogenic silent change.	PMID:16941501 PMID:21476993 PMID:25741868 gnomad_v2 gnomad_v4
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004655.4:c.1235A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Asn412Ser). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no pathogenic variant exists at residue Asn412; the only comparators are p.Asn412His (VUS), p.Asn412Thr and p.Asn412Ile (both conflicting).	pm5_candidates clinvar PMID:25741868
PM6	Not assessed	Not assessed: no source documents an apparently de novo occurrence for this variant, and zero parental genotypes exist to support even unconfirmed de novo status.	PMID:16941501 PMID:21476993 PMID:25741868
PP1	Not assessed	Not assessed: zero informative meioses or genotyped affected relatives are reported for this variant, so co-segregation cannot be evaluated.	PMID:16941501 PMID:21476993 PMID:25741868
PP2	Not met	Not met: AXIN2 shows no missense constraint (gnomAD o/e missense 1.03, mis_z -0.42) and its pathogenic variants are truncating, not missense.	clinvar gnomad_v2 gnomad_v4 pvs1_gene_context generic_acmg_combination_rules PMID:25741868
PP3	Not met	Not met: missense REVEL score 0.119 falls below the 0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: no proband phenotype or family history is recorded anywhere in this case, so PP4's single required input is unavailable.	PMID:25741868 generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar variation 136477 has zero expert-panel submissions (0 of 20; all is_expert_panel=false), so no expert-panel pathogenic assertion exists.	clinvar PMID:25741868 generic_acmg_combination_rules
BA1	Not met	Not met: the highest ancestry frequency, 4.11% in South Asians (gnomAD v4.1), and popmax filtering AF 4.0%, both stay below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1	Met	Met (strong): South Asian frequency 4.11% (3,565/86,704 alleles; 132 homozygotes) exceeds the 1% BS1 threshold, with a global frequency of 0.79% just below it.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:21476993
BS2	Not met	Not met: AXIN2-related disease is not fully penetrant at an early age, so healthy-adult carriers (4/275 controls) and 165 gnomAD homozygotes do not satisfy BS2's precondition.	gnomad_v2 gnomad_v4 PMID:25741868 PMID:21476993
BS3	Not met	Not met: the sole exact-variant test showed normal transcript proportions but is an n=1 splicing assay, not a validated test of AXIN2 protein function.	PMID:16941501 PMID:21476993 PMID:25741868
BS4	Not assessed	Not assessed: no genotyped pedigree exists for a non-segregation test; 4/275 healthy carrier controls are population-level, not family-based, evidence.	PMID:16941501 PMID:21476993 gnomad_v4 PMID:25741868
BP1	Met	Met (supporting): AXIN2 pathogenic variants are predominantly truncating (169 nonsense/frameshift vs 2 weak pathogenic-type missense records among 2,347 missense entries).	clinvar pvs1_gene_context oncokb generic_acmg_combination_rules PMID:25741868
BP2	Not met	Not met: the only variant co-inherited in cis with c.1235A>G is the non-pathogenic silent c.1530G>A, and no pathogenic allele in trans was reported.	PMID:16941501 PMID:21476993 PMID:25741868 clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004655.4:c.1235A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Asn412Ser). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at moderate strength: missense REVEL score 0.119 is at or below the 0.183 moderate BP4 threshold.	revel
BP5	Not met	Not met: no carrier of c.1235A>G has a documented alternate molecular basis for disease; the only worked-up carrier was APC/MMR-negative with no alternative cause reported.	PMID:16941501 PMID:21476993 clinvar PMID:25741868 generic_acmg_combination_rules
BP6	Not met	Not met: no ClinVar expert-panel Benign/Likely benign classification exists for this variant (0 of 20 submissions expert-panel; all is_expert_panel=false).	clinvar PMID:28492532 PMID:25741868 generic_acmg_combination_rules
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004655.4:c.1235A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Asn412Ser). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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