Variant classification summary

NM_000077.5:c.75A>G

CDKN2A · NP_000068.1:p.(Val25=) · NM_000077.5

GRCh37: chr9:21974752 T>C · GRCh38: chr9:21974753 T>C

Gene: CDKN2A Transcript: NM_000077.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.5

Protein

NP_000068.1:p.(Val25=)

gnomAD AF

6.829634155124585e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is 6.83e-06, below the 0.0001 threshold.

2

BP4 supporting: SpliceAI maximum delta score is 0.006, below the 0.1 threshold for synonymous variants.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion and one supporting benign criterion do not meet any benign, likely benign, likely pathogenic, or pathogenic combination, so the result 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	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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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 documented de novo observation with confirmed parental maternity, paternity, and parental test results.
PS3	Not assessed	Not assessed: no validated functional assay, control data, or variant-specific experimental result was identified for synonymous c.75A>G (p.Val25=).
PS4	Not assessed	Not assessed: no variant-specific affected-case/control counts or enrichment statistic are available for PS4.
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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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	Met	Met at supporting strength: gnomAD v4.1 allele frequency is 6.83e-06, below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic allele, or documented trans phase is available for NM_000077.5:c.75A>G.	generic_acmg_combination_rules
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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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 presumed de novo observation or affected-proband and parental evidence is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation data are documented.
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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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: synonymous variant SpliceAI max delta 0.006 is below the >=0.2 PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific phenotype-match evidence is documented for this exact variant.
PP5	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions and only non-expert benign assertions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 6.83e-06, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 6.83e-06, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no verified healthy-adult carrier observations required for BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no validated functional assay, control data, or variant-specific experimental result demonstrated preserved function for c.75A>G (p.Val25=).
BS4	Not assessed	Not assessed: no informative affected or unaffected relatives with genotype and phenotype data are reported.
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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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 pathogenic partner allele or documented cis/trans phase is reported for NM_000077.5:c.75A>G.	generic_acmg_combination_rules
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_000077.5:c.75A>G in CDKN2A is a synonymous (silent) substitution predicted to produce NP_000068.1:p.(Val25=). 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, supporting: synonymous variant SpliceAI max delta 0.006 meets the <=0.1 BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no established alternative molecular cause is documented to explain the patient's phenotype independently.
BP6	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions despite non-expert Benign or Likely benign labels.	clinvar
BP7	Not assessed	Not assessed: SpliceAI max delta is 0.006, but no evidence establishes that the synonymous position is not highly conserved.	spliceai

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