Variant classification summary

NM_000077.4:c.307_308insT

CDKN2A · NP_000068.1:p.(Arg103LeufsTer17) · NM_000077.4

GRCh37: chr9:21971050 C>CA · GRCh38: chr9:21971051 C>CA

Gene: CDKN2A Transcript: NM_000077.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate BP4 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.4

Protein

NP_000068.1:p.(Arg103LeufsTer17)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift predicted to trigger nonsense-mediated decay, a loss-of-function mechanism established in CDKN2A.

2

PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases.

3

BP4 (Supporting): no splice-altering effect predicted (SpliceAI/Pangolin max delta 0.00); applies to splicing only.

4

Combining PVS1 (very strong) plus PM2 (moderate) under generic ACMG/AMP 2015 rules yields Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback: 1 PVS1 (very strong) + 1 PM (moderate) combination yields Likely Pathogenic.

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	Met	Met at very strong: the frameshift creates a premature stop 17 codons after residue 103, predicted to trigger nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: as a frameshift it produces no altered amino acid to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or proband phenotype were available to test a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay evidence specific to this exact variant was available.
PS4	Not assessed	Not assessed: no variant-specific case series or case-control data were available.	generic_acmg_combination_rules
PM1	N/A	Not applicable: this criterion targets missense variants in hotspots; as a frameshift, no altered residue exists to evaluate.	generic_acmg_combination_rules
PM2	Met	Met at moderate: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence places this variant in trans with a pathogenic variant under a recessive inheritance model.
PM4	N/A	Not applicable: this criterion covers in-frame length changes; a frameshift produces no in-frame length change to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or proband phenotype was provided to confirm a de novo event without confirmed parentage.
PP1	Not assessed	Not assessed: no pedigree or relative genotype-phenotype data were available to evaluate segregation.
PP2	N/A	Not applicable: this criterion applies to missense variants; no missense change is present in this frameshift.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta score 0.00, far below splice-altering thresholds, and no missense score applies to a frameshift.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or personal/family cancer history was provided.	generic_acmg_combination_rules
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the standalone high-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population databases, so not more frequent than expected for a CDKN2A-related disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no carriers observed in healthy individuals; the variant is absent from all population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no variant-specific assay demonstrating normal protein function was available.
BS4	Not assessed	Not assessed: no genotype-phenotype data on affected relatives or evaluated unaffected carriers were available.
BP1	N/A	Not applicable: applies to missense variants in genes where truncating variants cause disease; no missense change is present.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no data document this variant in cis or in trans with another pathogenic or likely pathogenic variant.
BP3	N/A	Not applicable: applies to in-frame indels in repetitive regions; this frameshift does not qualify.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: SpliceAI/Pangolin max delta score 0.00, below the ~0.1 threshold, so no splice-altering effect is predicted. Flagged for human review: this covers splicing only and should not be read as broad benign support.	spliceai
BP5	Not assessed	Not assessed: no affected individual, phenotype attribution, or alternate molecular diagnosis was provided.	generic_acmg_combination_rules
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: applies to synonymous variants; this frameshift alters the encoded protein sequence.	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.