Variant classification summary

NM_000548.4:c.5335del

TSC2 · NP_000539.2:p.(Gln1779ArgfsTer47) · NM_000548.4

GRCh37: chr16:2138521 AC>A · GRCh38: chr16:2088520 AC>A

Gene: TSC2 Transcript: NM_000548.4

Final call

VUS

PVS1 supporting PM2 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Gln1779ArgfsTer47)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Supporting): terminal-exon frameshift escapes nonsense-mediated decay and alters only 29 of 1807 residues (~1.6% of tuberin), below the ~10% critical-region threshold.

2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with extreme rarity.

3

Combination: two supporting criteria under generic ACMG/AMP 2015 rules yield a VUS (variant of uncertain significance).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as 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	Met	Met (supporting): frameshift escapes nonsense-mediated decay in the terminal exon, altering only 29 of 1807 residues (~1.6%), far below the ~10% critical-region threshold.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: this frameshift produces no single altered amino acid to compare against a previously established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes, trio testing, or de novo documentation was available.
PS3	Not assessed	Not assessed: no functional assay results for this specific variant, with controls, were available.
PS4	Not assessed	Not assessed: no affected-case series, case-control comparison, or enrichment data for this variant was available.
PM1	N/A	Not applicable: this missense-only criterion requires a hotspot or critical-domain residue, which a frameshift does not provide.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with extreme rarity in TSC2-related disease.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: a recessive-allele criterion, but TSC2-associated tuberous sclerosis is autosomal dominant.
PM4	N/A	Not applicable: requires an in-frame indel or stop-loss length change; this frameshift does not qualify.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: requires a missense change at a residue with a known pathogenic missense; none exists for a frameshift.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no unconfirmed de novo observation in an affected proband was reported.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation analysis were documented.
PP2	N/A	Not applicable: this missense-variant criterion cannot apply to a frameshift with no missense change.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 shows no predicted splice impact for this frameshift variant.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or clinical diagnosis was available for evaluation.
PP5	Not assessed	Not assessed: the variant has no ClinVar entry or expert-panel assertion.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the stand-alone benign frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases rather than present above the benign disease-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no data on occurrence in healthy adults or homozygotes from population cohorts was available.
BS3	Not assessed	Not assessed: no variant-specific functional assay showing no damaging effect was available.
BS4	Not assessed	Not assessed: no unaffected carriers, non-segregation data, or phenotype-confirmed family dataset was provided.
BP1	N/A	Not applicable: this missense-variant criterion cannot apply to a frameshift in a truncation-driven gene.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant or phase information was documented for this variant.
BP3	N/A	Not applicable: requires an in-frame indel in a repetitive region; this frameshift does not qualify.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.00 suggests no splice disruption, but a benign splice score does not offset the frameshift's loss-of-function consequence.	spliceai
BP5	Not assessed	Not assessed: no evidence of an alternative genetic cause of the phenotype was available.
BP6	Not assessed	Not assessed: the variant is absent from ClinVar with no benign or likely-benign classification.	clinvar
BP7	N/A	Not applicable: this synonymous-variant criterion does not apply to a frameshift that alters the protein sequence.	generic_acmg_combination_rules

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