Variant classification summary

NM_001195132.1:c.44_46dupGGC

CDKN2A · NP_001182061.1:p.(Trp15_Leu16insArg) · NM_001195132.1

GRCh37: chr9:21974780 A>AGCC · GRCh38: chr9:21974781 A>AGCC

Gene: CDKN2A Transcript: NM_001195132.1

Final call

VUS

PM2 supporting PM4 moderate BP4 supporting

Variant details

Gene

CDKN2A

Transcript

NM_001195132.1

Protein

NP_001182061.1:p.(Trp15_Leu16insArg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, supporting rarity in reference populations.

2

PM4 (Moderate): the in-frame duplication inserts one arginine, lengthening p16INK4A from 156 to 157 residues in a non-repeat region, with no predicted splice impact.

3

BP4 (Supporting): SpliceAI predicts negligible splice impact (max delta 0.014, below the ~0.2 splice-altering threshold).

4

Overall: VUS — under generic ACMG/AMP 2015 combination rules, PM2 (supporting), PM4 (moderate), and BP4 (supporting) together reach no Pathogenic or Benign threshold.

Final determination: Generic ACMG/AMP 2015 fallback combination rules require thresholds like 2PS, PVS1+PM, 3PM, etc. for pathogenic calls, or BS+BP/2BP for benign calls; PM2(supporting)+PM4(moderate)+BP4(supporting) meets none, 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: in-frame insertion does not trigger a null-variant mechanism such as nonsense-mediated decay or truncation.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the in-frame insertion creates no single altered amino acid to compare with a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or de novo observation was documented.
PS3	Not assessed	Not assessed: no functional assay data for this variant was available.
PS4	Not assessed	Not assessed: no case-control enrichment or affected-case series data was available.	clinvar
PM1	N/A	Not applicable: no altered residue exists to evaluate for a mutational hotspot or critical functional domain.	generic_acmg_combination_rules
PM2	Met	Met (supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, supporting rarity.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of a pathogenic variant in trans or a recessive disease context was available.
PM4	Met	Met (moderate): the in-frame duplication inserts one arginine, lengthening p16INK4A from 156 to 157 residues in a non-repeat region.	pvs1_variant_assessment spliceai generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a previously pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no presumed de novo occurrence without confirmed parentage was documented.
PP1	Not assessed	Not assessed: no family segregation or affected-relative data was available.
PP2	N/A	Not applicable: no missense change is present, so missense-constraint assessment does not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta score 0.014, well below the ~0.2 splice-altering threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or CDKN2A-specific clinical presentation was documented.	clinvar
PP5	Not met	Not met: the ClinVar record has no expert-panel submission, only single-laboratory assertions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the stand-alone benign frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, no allele frequency above the disease-prevalence threshold is demonstrated.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no evidence of the variant in healthy adults or homozygous individuals was provided.
BS3	Not assessed	Not assessed: no functional assay showing normal, wild-type-like activity was available.
BS4	Not assessed	Not assessed: no unaffected-relatives or non-segregation data was available.
BP1	N/A	Not applicable: no missense change is present, so the truncating-variant mechanism premise does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no genotype data establishing trans or cis configuration with a pathogenic variant was available.
BP3	Not met	Not met: the duplicated unit lies outside a repeat region, and CDKN2A has well-established function.	pvs1_variant_assessment spliceai generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI predicts negligible splice impact (max delta 0.014, below the ~0.2 splice-altering threshold).	spliceai
BP5	Not assessed	Not assessed: no alternative pathogenic variant or molecular workup explaining the phenotype was provided.
BP6	Not met	Not met: the ClinVar record has no expert-panel Benign or Likely benign submission.	clinvar
BP7	N/A	Not applicable: the protein sequence is altered, so the synonymous-variant premise does not apply.	generic_acmg_combination_rules

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