Variant classification summary

NM_000075.4:c.122A>G

CDK4 · NP_000066.1:p.(Asn41Ser) · NM_000075.4

GRCh37: chr12:58145379 T>C · GRCh38: chr12:57751596 T>C

Gene: CDK4 Transcript: NM_000075.4

Final call

VUS

PM2 supporting BP4 moderate

Variant details

Gene

CDK4

Transcript

NM_000075.4

Protein

NP_000066.1:p.(Asn41Ser)

gnomAD AF

0.000253407054753272 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): rare in population databases - gnomAD v4.1 allele frequency 0.02534% with no homozygotes, below the 0.1% rare-variant cutoff.

2

BP4 (Moderate): REVEL 0.113, at or below the 0.183 benign-supporting/moderate cutoff, predicting a benign-leaning missense effect; SpliceAI corroborates (max delta 0.061).

3

Overall classification: VUS - PM2 (supporting) and BP4 (moderate) point in opposite directions, so no ACMG/AMP 2015 combination rule is satisfied.

Final determination: PM2 supporting + BP4 moderate is conflicting evidence meeting no generic ACMG/AMP combination threshold, defaulting to 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	Not applicable: missense substitution (p.Asn41Ser), so no null-variant mechanism such as nonsense-mediated decay or truncation is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical amino acid change p.Asn41Ser via a different nucleotide substitution was identified.
PS2	Not assessed	Not assessed: no confirmed de novo occurrence of p.Asn41Ser with verified maternity and paternity was documented.
PS3	Not assessed	Not assessed: no validated functional assay (e.g., kinase activity, Rb phosphorylation) specifically testing p.Asn41Ser was available.
PS4	Not assessed	Not assessed: no case-control enrichment analysis or count of unrelated affected carriers of p.Asn41Ser was available.	PMID:28135145
PM1	Not met	Not met: not in a statistically significant hotspot - cancerhotspots.org found no result and COSMIC shows a single somatic observation (n=1).
PM2	Met	Met (supporting): rare in gnomAD v4.1 - allele frequency 0.02534%, below the 0.1% cutoff, with no homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observation in a recessive disorder, no second pathogenic variant, and no phasing evidence were available.	clinvar
PM4	N/A	Not applicable: missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic amino acid changes at codon 41 (same-residue comparators) were identified.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence of p.Asn41Ser with sufficient phenotype and family context was documented.
PP1	Not assessed	Not assessed: no segregation data - affected or unaffected relatives, informative meioses, or genotype-phenotype results - were available.
PP2	Not assessed	Not assessed: no gene-level missense constraint metric (e.g., missense Z-score or o/e ratio) was available for CDK4.
PP3	Not met	Not met: REVEL 0.113, far below the 0.644 pathogenic-supporting cutoff; SpliceAI max delta 0.061.	revel spliceai
PP4	Not assessed	Not assessed: no patient-specific phenotype establishing CDK4-related disease specificity was provided.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic submission exists for this variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.02534% (max subpopulation 0.06598%), below the 1% stand-alone threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest gnomAD v4.1 subpopulation frequency 0.06598%, below the 0.3% benign threshold.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1 and v4.1, and no documented series of healthy adult carriers.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no well-established functional assay showing no damaging effect of p.Asn41Ser on CDK4 was available.
BS4	Not assessed	Not assessed: no unaffected relatives with reliable phenotype assessment and confirmed absence of the variant were documented.
BP1	Not assessed	Not assessed: without a gene-specific framework, CDK4's disease mechanism could not be established to evaluate this missense variant.
BP2	Not assessed	Not assessed: no genotype, inheritance, or phase information was available to evaluate the variant's configuration.	clinvar
BP3	N/A	Not applicable: missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (moderate): REVEL 0.113, at or below the 0.183 benign-supporting/moderate cutoff; SpliceAI max delta 0.061, no splice impact.	revel spliceai
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the patient's phenotype was documented.
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign submission exists for this variant.	clinvar
BP7	N/A	Not applicable: missense substitution, so the criterion's silent-variant premise does not hold.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.