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

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

Variant of uncertain significance: no pathogenic or benign criteria were met under generic ACMG/AMP 2015 combination rules, with no CDK4-specific framework available.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds; therefore the final call is 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	Not applicable: this missense substitution (p.Arg246Cys) is not a nonsense, frameshift, or canonical splice variant, which PVS1 requires.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant shares the p.Arg246Cys amino-acid change, and the ClinVar record for this variant remains uncertain significance.	clinvar
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo observation is available.
PS3	Not assessed	Not assessed: no validated functional assay exists; the only study reports in-silico docking and molecular dynamics rather than experimental protein function.	PMID:26252490 oncokb
PS4	Not assessed	Not assessed: no case-control or statistically valid enrichment data link this variant to disease.	PMID:26252490 PMID:25394175
PM1	Not assessed	Not assessed: no mutational hotspot or critical functional domain is established for CDK4 Arg246.
PM2	Not met	Not met: the variant is present in gnomAD v4.1 at 9.91e-06 (16/1,614,036 alleles), so it is not absent from population databases.	gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: no recessive CDK4 disorder or compound-heterozygous phase data are available; CDK4 melanoma risk is autosomal dominant.	generic_acmg_combination_rules
PM4	N/A	Not applicable: the missense change p.Arg246Cys does not alter protein length, so PM4 has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no confirmed pathogenic missense variant at CDK4 residue 246 is available for comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no suspected de novo occurrence or parental testing is reported for this variant.
PP1	Not assessed	Not assessed: no affected relatives carrying this exact variant or segregation data are available.
PP2	Not assessed	Not assessed: CDK4 is not established as a gene where missense variation is a well-understood disease mechanism with benign missense variation rare.
PP3	Not met	Not met: REVEL 0.386 sits in the 0.25-0.75 gray zone, below the >0.75 PP3 computational-support threshold.	revel PMID:26252490
PP4	Not assessed	Not assessed: no individual phenotype is provided, and this variant is not linked to a highly specific CDK4-associated phenotype.	PMID:25394175
PP5	Not met	Not met: the exact ClinVar record has no expert-panel submission and no pathogenic or likely pathogenic expert classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 frequency 9.91e-06 is far below the 5% stand-alone benign threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: maximum population frequency 3.33e-05 is not higher than expected for a rare, high-penetrance hereditary melanoma allele.	gnomad_v4 gnomad_v2 PMID:25394175
BS2	Not assessed	Not assessed: there are zero homozygotes, but CDK4 melanoma risk is autosomal dominant and no healthy adult carrier data exist.	gnomad_v4 gnomad_v2 PMID:25394175
BS3	Not assessed	Not assessed: no experimental assay demonstrates preserved normal protein function; the only available study is computational.	PMID:26252490 oncokb
BS4	Not assessed	Not assessed: no unaffected at-risk relatives were tested for this variant, so non-segregation cannot be shown.
BP1	Not assessed	Not assessed: CDK4 disease is not established as predominantly truncating with missense variation generally benign.
BP2	Not assessed	Not assessed: no family genotypes or phase data establish this variant in trans or in cis with a pathogenic variant.	generic_acmg_combination_rules
BP3	N/A	Not applicable: the missense change p.Arg246Cys does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.386 is above the <0.25 BP4 threshold and lies within the 0.25-0.75 gray zone.	revel
BP5	Not assessed	Not assessed: no alternative molecular cause or second diagnosis is reported for this individual.
BP6	Not met	Not met: the exact ClinVar record has no expert-panel submission and no benign or likely benign expert classification.	clinvar
BP7	N/A	Not applicable: the missense change p.Arg246Cys alters the encoded protein sequence, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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