Variant classification summary

NM_000075.4:c.736C>T

CDK4 · NP_000066.1:p.(Arg246Cys) · NM_000075.4

GRCh37: chr12:58143048 G>A · GRCh38: chr12:57749265 G>A

Gene: CDK4 Transcript: NM_000075.4

Final call

VUS

PM2 supporting

Variant details

Gene

CDK4

Transcript

NM_000075.4

Protein

NP_000066.1:p.(Arg246Cys)

gnomAD AF

9.913037875239462e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 AF 9.91304e-06 is below the generic threshold of 0.0001, with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any definitive pathogenic, likely pathogenic, likely benign, or benign combination, so the call 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_000075.4:c.736C>T in CDK4 is a missense substitution predicted to produce NP_000066.1:p.(Arg246Cys). 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 available report describes the exact c.736C>T change, not a different nucleotide substitution producing CDK4 p.Arg246Cys.	PMID:26252490
PS2	Not assessed	Not assessed: no documented proband-parent genotypes or confirmed de novo testing are available for CDK4 c.736C>T.	PMID:26252490
PS3	Not assessed	Not assessed: the only variant-specific study used computational predictions and molecular dynamics, not a validated functional assay with experimental controls.
PS4	Not assessed	Not assessed: no case-control counts or validated enrichment statistic is available for the exact CDK4 c.736C>T variant.	clinvar PMID:26252490
PM1	Not assessed	Not assessed: no approved CDK4 domain table or residue-specific hotspot evidence establishes that Arg246 lies in a PM1-qualifying critical region.
PM2	Met	Met at supporting strength: gnomAD v4.1 AF 9.91304e-06 is below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic allele, phase result, or validated recessive CDK4 inheritance context is available.	PMID:26252490
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_000075.4:c.736C>T in CDK4 is a missense substitution predicted to produce NP_000066.1:p.(Arg246Cys). 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 assessed	Not assessed: no independently classified pathogenic alternate missense change at CDK4 residue Arg246 was documented.	PMID:26252490
PM6	Not assessed	Not assessed: no documented presumed de novo occurrence or parental testing context is available for CDK4 c.736C>T.	PMID:26252490
PP1	Not assessed	Not assessed: zero informative family meioses or variant-positive and variant-negative relatives are documented for CDK4 c.736C>T.	PMID:26252490
PP2	Not assessed	Not assessed: the evidence lacks validated CDK4 missense-mechanism and benign-missense-constraint data required for PP2.	PMID:26252490
PP3	Not met	Not met: REVEL 0.386 is below the supporting PP3 threshold of 0.644, and BayesDel lacks an applicable generic calibration.	revel bayesdel spliceai PMID:26252490
PP4	Not assessed	Not assessed: no patient phenotype, family history, or disease-specific clinical presentation is documented for this exact variant.	PMID:26252490
PP5	Not met	Not met: the exact-variant ClinVar record has zero expert-panel submissions and an aggregate Uncertain significance classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 overall AF 9.91304e-06 is far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest reported gnomAD v4.1 population AF is 3.33322e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes among 16 observed variant alleles, with no qualifying healthy-carrier observation provided.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated controlled assay demonstrates normal CDK4 p.Arg246Cys function; the available study is computational only.
BS4	Not assessed	Not assessed: no tested unaffected relatives lacking CDK4 c.736C>T or informative non-segregation observations are documented.	PMID:26252490
BP1	Not assessed	Not assessed: no validated CDK4 framework shows truncating variants predominate while missense variants are generally benign.
BP2	Not assessed	Not assessed: no second pathogenic variant, cis/trans phase determination, affected-proband genotype, or family segregation result is available.	PMID:26252490
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_000075.4:c.736C>T in CDK4 is a missense substitution predicted to produce NP_000066.1:p.(Arg246Cys). 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	Not met	Not met: REVEL 0.386 exceeds the supporting BP4 threshold of 0.29, while BayesDel has no applicable generic benign calibration.	revel bayesdel spliceai PMID:26252490
BP5	Not assessed	Not assessed: no patient phenotype or alternative pathogenic molecular explanation is documented for this case.	PMID:26252490
BP6	Not met	Not met: no exact-variant ClinVar expert panel classified this variant as Benign or Likely benign.	clinvar
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_000075.4:c.736C>T in CDK4 is a missense substitution predicted to produce NP_000066.1:p.(Arg246Cys). 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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