Variant classification summary

NM_004655.4:c.2433G>A

AXIN2 · NP_004646.3:p.(Glu811=) · NM_004655.4

GRCh37: chr17:63526193 C>T · GRCh38: chr17:65530075 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.(Glu811=)

gnomAD AF

0.00012327874377101623 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: SpliceAI max delta 0.003 predicts no splice impact for this synonymous AXIN2 variant.

Final determination: Under the generic ACMG/AMP 2015 combination rules, one supporting benign criterion (BP4) is below the two-supporting Likely Benign threshold and no pathogenic combination is satisfied, so the variant is classified as Variant of Uncertain Significance.

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.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). 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	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004655.4:c.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2	Not assessed	Not assessed: no parental-tested proband or de novo report in any of 12 ClinVar submissions for AXIN2 c.2433G>A.	clinvar PMID:25741868 PMID:26467025
PS3	Not met	Not met: no functional assay of AXIN2 c.2433G>A exists in the record, and SpliceAI max delta 0.003 is in-silico, not a validated assay.	generic_acmg_combination_rules PMID:25741868 PMID:26467025 pvs1_gene_context
PS4	Not met	Not met: no cohort or case-control enrichment data report c.2433G>A in affected individuals, and the generic ACMG PS4 rule sets no numeric threshold.	generic_acmg_combination_rules clinvar gnomad_v4 PMID:25741868 PMID:25394175 PMID:26467025
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004655.4:c.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2	Not met	Not met: gnomAD v4.1 total allele frequency 1.23e-4 and grpmax filtering frequency 1.35e-4 both exceed the 1e-4 PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not assessed	Not assessed: no proband genotype, second allele, or phase determination exists, and AXIN2 disease is dominant rather than recessive.	generic_acmg_combination_rules clinvar gnomad_v4 gnomad_v2
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.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). 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	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004655.4:c.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6	Not assessed	Not assessed: no proband or parental samples reported, so an assumed-but-unconfirmed de novo event cannot be evaluated for this variant.	clinvar PMID:25741868 PMID:26467025
PP1	Not assessed	Not assessed: no pedigree or genotyped relatives; zero segregation evidence for AXIN2 c.2433G>A among 12 ClinVar submissions and the papers reviewed.	clinvar PMID:25741868 PMID:26467025
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004655.4:c.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3	Not met	Not met: SpliceAI max delta 0.003 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, scored on the splice path only.	spliceai pvs1_variant_assessment generic_acmg_combination_rules final_classification_framework PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype or HPO data were provided for this case, so phenotype specificity could not be evaluated.	PMID:25741868 final_classification_framework
PP5	Not met	Not met: the exact variant has no ClinVar expert-panel submission (0 of 12 audited submissions), so the expert-panel gate for PP5 is unmet.	clinvar PMID:25741868 PMID:25394175 final_classification_framework
BA1	Not met	Not met: the highest observed allele frequency is 1.94e-4 (European non-Finnish, gnomAD v2.1), over two orders of magnitude below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed allele frequency, 1.94e-4 (European non-Finnish, gnomAD v2.1), is roughly 50-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1/v4.1, and AXIN2 disease is adult-onset with incomplete penetrance, so healthy-adult observations do not satisfy BS2.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS3	Not met	Not met: no functional study of AXIN2 c.2433G>A showed normal function or splicing; benign ClinVar status and SpliceAI 0.003 are not assay evidence.	generic_acmg_combination_rules PMID:25741868 PMID:26467025 pvs1_gene_context
BS4	Not assessed	Not assessed: no affected-relative genotypes reported, so lack of segregation cannot be shown from the 12 ClinVar submissions or the papers reviewed.	clinvar PMID:25741868 PMID:26467025
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004655.4:c.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2	Not assessed	Not assessed: no second variant, proband genotype, or cis/trans phase result exists, so no allelic configuration with a pathogenic variant is established.	generic_acmg_combination_rules clinvar gnomad_v4 spliceai
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.2433G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Glu811=). 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 supporting strength: SpliceAI max delta 0.003 is below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.	spliceai pvs1_variant_assessment generic_acmg_combination_rules final_classification_framework PMID:25741868
BP5	Not assessed	Not assessed: no case-level data on an alternate molecular basis for disease were available for this individual.	PMID:25741868 final_classification_framework
BP6	Not met	Not met: no ClinVar expert panel has submitted on this exact variant (0 of 12 audited submissions); ordinary laboratory Benign/Likely benign labels cannot trigger BP6.	clinvar PMID:25741868 final_classification_framework
BP7	Not met	Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.003, is already credited under BP4, and no conservation data is available.	spliceai pvs1_variant_assessment generic_acmg_combination_rules final_classification_framework PMID:25741868

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