Variant classification summary

NM_000548.5:c.1292C>T

TSC2 · NP_000539.2:p.(Ala431Val) · NM_000548.5

GRCh37: chr16:2112532 C>T · GRCh38: chr16:2062531 C>T

Gene: TSC2 Transcript: NM_000548.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.(Ala431Val)

gnomAD AF

0.00016559762134832438 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): present but extremely rare in population databases — gnomAD v4.1 allele frequency 0.0166%, below the 0.1% rare-variant threshold, with no homozygotes.

2

BP4 (Supporting): SpliceAI predicts no splicing impact, with a maximum delta score of 0.005, far below splice-altering thresholds.

3

Overall: VUS — PM2 (supporting) and BP4 (supporting) satisfy no ACMG/AMP 2015 combination rule.

Final determination: Generic ACMG/AMP 2015 combination rules require at least (2 PS), (1 PVS1 + 1 PM/PS), (3 PM), or equivalent for pathogenic, and (1 BA1), (2 BS), (1 BS+1 BP), or (2 BP) for benign; a single PM2-supporting plus BP4-supporting satisfies none of these, 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: this is a missense change (p.Ala431Val), so the null-variant mechanisms PVS1 addresses are not triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no different nucleotide change at codon 431 producing the same p.Ala431Val change was found.
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo observation for p.Ala431Val is documented.	PMID:23514105
PS3	Not assessed	Not assessed: no validated functional assay (e.g., GAP-domain or mTOR pathway activity) has been reported for p.Ala431Val.
PS4	Not assessed	Not assessed: no case-control data provide carrier counts or an enrichment statistic for this exact variant.	PMID:23514105 PMID:22558107
PM1	Not assessed	Not assessed: no mutational-hotspot or functional-domain data characterize residue 431 in TSC2.
PM2	Met	Met (supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 0.0166%, below the 0.1% threshold, and no homozygotes reported.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3	N/A	Not applicable: PM3 requires a recessive disease, but TSC2-related tuberous sclerosis is autosomal dominant.
PM4	N/A	Not applicable: no protein length change occurs, since this is a missense substitution rather than an indel or stop-loss variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense change at residue 431 with an established pathogenic classification was identified.
PM6	Not assessed	Not assessed: no de novo observation, confirmed or unconfirmed, is documented for this variant.	PMID:23514105
PP1	Not assessed	Not assessed: no family segregation data (affected or unaffected relatives, meioses) are reported for this variant.	PMID:23514105
PP2	Not assessed	Not assessed: TSC2 missense-constraint data are unavailable, and its disease mechanism is primarily truncating loss-of-function.
PP3	Not met	Not met: SpliceAI max delta 0.005 predicts no splice effect, and REVEL 0.386 is below the 0.644 PP3 threshold.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no proband phenotype highly specific for tuberous sclerosis is documented for this variant.	PMID:23514105
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely Pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: highest population allele frequency is 0.056% (Finnish, gnomAD v4.1), below the 1% benign-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: gnomAD v4.1 allele frequency 0.0166% (maximum subpopulation 0.056%) is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy-adult homozygote or hemizygote observation is documented for this variant.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay demonstrating a lack of damaging effect has been reported for this variant.
BS4	Not assessed	Not assessed: no family-based non-segregation data are available for this variant.	PMID:23514105
BP1	Not assessed	Not assessed: evidence is insufficient to determine whether missense is an established disease mechanism in TSC2.
BP2	Not assessed	Not assessed: no phase information (in trans or in cis with a pathogenic variant) is available.	PMID:23514105
BP3	N/A	Not applicable: BP3 concerns in-frame indels in repetitive regions, and this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI predicts no splicing impact, with a maximum delta score of 0.005, far below splice-altering thresholds.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no independent molecular cause fully explaining the affected individual's phenotype was identified.
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely Benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants, and this is a missense change.	generic_acmg_combination_rules

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