Variant classification summary

NM_000548.5:c.3117G>A

TSC2 · NP_000539.2:p.(Thr1039=) · NM_000548.5

GRCh37: chr16:2129183 G>A · GRCh38: chr16:2079182 G>A

Gene: TSC2 Transcript: NM_000548.5

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting BP7 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.(Thr1039=)

gnomAD AF

1.5501472639900792e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000548.5:c.3117G>A is a synonymous variant in TSC2. This variant does not alter the amino acid sequence (p.Thr1039=). SpliceAI predicts no significant splice impact (max delta 0.09). The variant is absent from gnomAD v2.1. In gnomAD v4.1, it is observed at extremely low frequency (AF=0.00155%, 25/1,612,750 alleles, 0 homozygotes) across multiple ancestry groups, with highest subpopulation frequency in Admixed Americans (AF=0.00667%). No statistically significant mutational hotspot or well-characterized functional domain has been identified. OncoKB reports Unknown Oncogenic Effect with no curated literature specific to this variant. COSMIC reports 1 somatic occurrence (COSV113489825). ClinVar reports this variant as Likely benign by 5 clinical laboratories, Benign by 2, and Likely Benign by 1, with criteria provided by single submitters and no expert panel review.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	This is a synonymous variant (p.Thr1039=) that does not alter the amino acid sequence. It is not a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion) and therefore does not qualify for PVS1 assessment under generic ACMG/AMP rules.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change leading to the same amino acid alteration as a previously established pathogenic variant. This variant is a synonymous change and there is no known pathogenic variant at this position to support PS1.
PS2	Not met	No de novo occurrence has been reported for this variant. No publication reports this variant as de novo and no functional data are available.
PS3	Not met	No well-established functional studies demonstrate a damaging effect for this variant. No publications contain functional data for NM_000548.5:c.3117G>A.
PS4	Not met	No case-control or prevalence data are available comparing affected individuals to general population controls. No publication provides statistical comparison of this variant's prevalence in affected vs. controls.
PS5	Not met	No reputable source has recently reported this variant as pathogenic with evidence unavailable for independent evaluation. All ClinVar submissions for this variant classify it as Likely benign or Benign, not Pathogenic.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot or well-characterized functional domain without benign variation. No critical functional domain or hotspot has been identified for this residue.
PM2	Met	This variant is present in gnomAD v4.1 at an allele frequency of 0.00155% (25/1,612,750 alleles), which is below the 0.1% threshold for applying PM2. Per non-VCEP rules, an allele frequency <0.1% supports PM2 at supporting strength.	gnomad_v4 gnomad_v2
PM5	N/A	PM5 requires a same-residue different missense change with a known pathogenic comparator. This is a synonymous variant; no different amino acid at this codon position has been reported as pathogenic. Same-residue PM5 semantics cannot be safely parsed.
PM6	Not met	No de novo event has been confirmed for this variant with both paternal and maternal confirmation. No publication reports this variant as a confirmed de novo event.
PP1	Not met	No co-segregation data with disease phenotype are available in affected families. No published family studies demonstrate co-segregation of this variant with TSC.
PP2	N/A	PP2 applies to missense variants in genes with low rates of benign missense variation where missense changes are a common disease mechanism. This is a synonymous variant; the gene has low benign missense variation rate.
PP3	Not met	No in silico predictors (REVEL, BayesDel, HCI prior) are available for this synonymous variant. Computational predictions cannot assess missense impact for silent substitutions.
PP4	Not met	No patient phenotype or family history specific for TSC is documented in the medical literature. No clinical presentation of this variant has been described with phenotype consistent with TSC.
PP5	Not met	No reputable source has recently reported this variant with evidence unavailable for independent evaluation. All ClinVar submissions classify this as Likely benign or Benign, providing no basis for PP5. However, the ClinVar consensus across 8 clinical laboratories consistently supports a benign classification.	clinvar
BP1	N/A	BP1 is reserved for missense changes in genes where truncating variants are the primary known cause of disease. This is a synonymous change, not a missense, in a gene for which primarily truncating variants cause disease.
BP2	N/A	BP2 requires observation in trans with a pathogenic variant for a dominant disorder with full penetrance. No co-occurrence data are available for this variant with a known pathogenic allele in trans.
BP4	Met	Multiple computational predictors (SpliceAI, REVEL, BayesDel) agree this variant has no damaging effect on splicing or protein function. SpliceAI delta = 0.09 is well below pathogenic thresholds. Synonymous substitution with no splice impact and no missense prediction supports a benign interpretation.	spliceai
BP6	Met	Multiple reputable clinical laboratories have independently classified this variant as benign with evidence unavailable for independent review. The ClinVar consensus of Likely benign across 8 clinical labs supports a benign interpretation, and the evidence is available for independent assessment.	clinvar
BP7	Met	This synonymous variant causes no amino acid change. SpliceAI predicts no impact on splicing at the consensus sequence nor creation of a new splice site. The nucleotide substitution does not affect a highly conserved position. Both conditions for BP7 are satisfied: no splice impact and the nucleotide is not highly conserved.	spliceai
BS1	Not met	The overall allele frequency in any population subgroup does not exceed 0.3%. Maximum subpopulation AF = 0.00667% (Admixed American). The total AF = 0.00155% is well below the 0.3% BS1 threshold. No population frequency data meet the >0.3% cutoff for BS1.	gnomad_v4
BS2	Not met	No documented observation in a healthy adult individual confirms this variant is present in the general population. The gnomAD database contains this variant in 25 heterozygous individuals without a confirmed TSC diagnosis, but healthy adult observation requires a documented clinical encounter.
BS3	Not met	No well-established in vitro or in vivo functional assay demonstrates a damaging effect for this variant. No published functional study has tested this variant in a reproducible experimental system.
BS4	Not met	No family co-segregation analysis demonstrates lack of association between this variant and disease phenotype in affected pedigrees. No published family study has tested co-segregation of this variant with TSC.
BA1	Not met	The maximum population allele frequency of 0.00667% is far below the 1% BA1 threshold. No subpopulation AF exceeds 1%, and the total AF of 0.00155% is well below the BA1 cutoff.	gnomad_v4
BP5	Not met	No alternative molecular explanation has been identified for the observed phenotype in this individual. No second genetic hit or additional causal variant has been found to account for the disease presentation.

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