TSC2c.3117G>ALikely benign

Print report

Variant interpretation report

TSC2 c.3117G>A, p.(Thr1039=)

NM_000548.5:c.3117G>A NP_000539.2:p.(Thr1039=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TSC2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 5 Likely benign · 2 Benign · 1 Likely Benign
Pipeline record: 26 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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.
BP4 (supporting): 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.
BP6 (supporting): 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.
BP7 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 3

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 3

BP4Supporting

BP4 · supporting

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.

BP6Supporting

BP6 · supporting

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.

BP7Supporting

BP7 · supporting

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.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP6 supporting, BP7 supporting; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

25 / 1,612,750 alleles

gnomAD v4.1: 25 / 1,612,750 alleles. Recorded AF 1.55015e-05. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.090 maximum delta

Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

8 reported laboratory submissions

5 Likely benign · 2 Benign · 1 Likely Benign.

Applied · BP6 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV113489825, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 16 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 4

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

PM2_supporting — gnomAD v4.1 AF = 0.00155% (25/1
612
750 alleles
0 homozygotes). AF is extremely low but below the PM2 threshold for population databases.

Sources

gnomad_v4 ↗gnomad_v2 ↗

BP4 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

BP4_supporting — SpliceAI max delta 0.09
no significant splice impact predicted. Synonymous variant with no amino acid change
computational consensus supports no damaging effect.

Sources

spliceai ↗

BP6 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

BP6_supporting — ClinVar consensus Likely benign
8 clinical laboratories agree
evidence available for independent evaluation.

Sources

clinvar ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Evidence considered

BP7_supporting — synonymous silent variant
SpliceAI max delta 0.09 predicts no splice impact
nucleotide not highly conserved.

Still missing

Nucleotide conservation data not available.

Sources

spliceai ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo occurrence has been reported for this variant. No publication reports this variant as de novo and no functional data are available. Details ▾Hide ▴

Evidence considered

PS2 not met — no de novo data available for this variant.

Still missing

No de novo reports
parental confirmation data
or functional studies available.

PS3 No well-established functional studies demonstrate a damaging effect for this variant. No publications contain functional data for NM_000548.5:c.3117G>A. Details ▾Hide ▴

Evidence considered

PS3 not met — no functional evidence available for this specific variant.

Still missing

No published functional studies available for this variant.

PS4 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. Details ▾Hide ▴

Evidence considered

PS4 not met — no prevalence data available for this variant.

Still missing

No affected-vs-control data available in published literature.

PM1 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. Details ▾Hide ▴

Evidence considered

PM1 not met — no hotspot or functional domain data available.

PM6 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. Details ▾Hide ▴

Evidence considered

PM6 not met — no confirmed de novo event data available.

Still missing

No confirmed de novo reports or parental studies available.

PP1 No co-segregation data with disease phenotype are available in affected families. No published family studies demonstrate co-segregation of this variant with TSC. Details ▾Hide ▴

Evidence considered

PP1 not met — no family segregation data available for this variant.

Still missing

No co-segregation or family studies available.

PP3 No in silico predictors (REVEL, BayesDel, HCI prior) are available for this synonymous variant. Computational predictions cannot assess missense impact for silent substitutions. Details ▾Hide ▴

Evidence considered

PP3 not met — no in silico scores available for synonymous variants.

Still missing

REVEL
BayesDel
and HCI prior not available for synonymous variants.

PP4 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. Details ▾Hide ▴

Evidence considered

PP4 not met — no patient-specific or phenotype data available.

Still missing

No clinical phenotype data or familial disease history available.

PP5 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. Details ▾Hide ▴

Evidence considered

PP5 not met — ClinVar consensus is Likely benign/Benign
no submitter classifies as Pathogenic.

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

BA1 not met — gnomAD v4.1 max AF = 0.00667%
total AF = 0.00155%
no frequency >1%. BA1 threshold not reached.

Sources

gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

BS1 not met — gnomAD v4.1 max subpopulation AF = 0.00667% (AMR)
total AF = 0.00155%
no population exceeds 0.3% threshold.

Sources

gnomad_v4 ↗

BS2 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. Details ▾Hide ▴

Evidence considered

BS2 not met — no healthy adult observation or clinical documentation of this specific variant.

Still missing

No documented healthy individual with this variant in clinical databases.

BS3 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. Details ▾Hide ▴

Evidence considered

BS3 not met — no functional data available for this variant.

Still missing

No published functional studies available for this specific variant.

BS4 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. Details ▾Hide ▴

Evidence considered

BS4 not met — no co-segregation or family linkage data available.

Still missing

No family studies or meiotic recombination data available.

BP5 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. Details ▾Hide ▴

Evidence considered

BP5 not met — no alternative molecular basis identified for this phenotype.

Still missing

No alternate cause or second mutation identified.

PS5 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. Details ▾Hide ▴

Evidence considered

PS5 not met — ClinVar classification is consistently Likely benign/Benign across 8 clinical laboratories
with no submitter classifying as Pathogenic.

Sources

clinvar ↗

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant c.3117G>A
no protein change (p.Thr1039=). PVS1 is not applicable — variant is not a null variant type.

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PS1 N/APS1 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. Details ▾Hide ▴

Evidence considered

PS1 not applicable — variant is synonymous
no reference pathogenic variant at same position available.

PM5 N/APM5 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. Details ▾Hide ▴

Evidence considered

PM5 not applicable — synonymous variant with no known pathogenic comparator at this residue.

PP2 N/APP2 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. Details ▾Hide ▴

Evidence considered

PP2 not applicable — synonymous variant with no established gene-level constraint.

BP1 N/ABP1 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. Details ▾Hide ▴

Evidence considered

BP1 not applicable — synonymous variant
gene has primarily truncating mechanism.

BP2 N/ABP2 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. Details ▾Hide ▴

Evidence considered

BP2 not applicable — no trans configuration data for this variant.

Still missing

No co-occurrence or allelic phase data available.

Identifiers

Gene: TSC2
Transcript: NM_000548.5
Coding (HGVS c.): NM_000548.5:c.3117G>A
Protein (HGVS p.): NP_000539.2:p.(Thr1039=)
GRCh38: chr16:2079182 G>A
GRCh37: chr16:2129183 G>A
ClinVar: 4557755, 4071151, 2497441, 2075111, 1086546, 708092, 452788
COSMIC: COSV113489825

Gene diagram

Every interpreted variant in TSC2, mapped onto the exon structure of NM_000548.5. Select a row to find it on the plot.

TSC2NM_000548.5

Fetching transcript structure from UCSC…

Exons

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Transcript span

—

Strand

—

Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in TSC2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 25 / 1,612,750 alleles AF 1.55e-05 · 0 homozygotes · FAF 2.26e-05

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.6e-05 · 25 / 1,612,750 alleles · 0 hom · FAF 2.3e-05

Admixed American4 / 59,996	6.7e-05
South Asian5 / 91,090	5.5e-05
Remaining individuals2 / 62,468	3.2e-05
European (non-Finnish)14 / 1,180,022	1.2e-05

0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.55015e-05; MAF= 0.00155%, 25/1612750 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.66711e-05; MAF= 0.00667%, 4/59996 alleles, homozygotes = 0); grpmax FAF= 2.255e-05.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -106 bp

0.000

SpliceAI acceptor gainat +94 bp

0.020

SpliceAI donor lossat +14 bp

0.090

SpliceAI donor gainat +246 bp

0.010

Pangolin splice lossmagnitude shown

-0.040

Pangolin splice gain

0.070

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

BP4_supporting — SpliceAI max delta 0.09
no significant splice impact predicted. Synonymous variant with no amino acid change
computational consensus supports no damaging effect.

Sources

spliceai ↗

Evidence considered

BP7_supporting — synonymous silent variant
SpliceAI max delta 0.09 predicts no splice impact
nucleotide not highly conserved.

Still missing

Nucleotide conservation data not available.

Sources

spliceai ↗

Evidence considered

PP3 not met — no in silico scores available for synonymous variants.

Still missing

REVEL
BayesDel
and HCI prior not available for synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015

Richards et al. (2015) provides the ACMG/AMP standards and guidelines for sequence variant interpretation. This framework document does not discuss the specific variant NM_000548.5:c.3117G>A or any individual gene.
Does not name this variant
PMID 25741868 ↗
Tuberous Sclerosis Complex.

Adam MP et al. · 1993

Adam et al. GeneReviews entry on Tuberous Sclerosis Complex. This clinical synopsis covers TSC1 and TSC2 genes at the disease level, but does not discuss the specific variant NM_000548.5:c.3117G>A.
Does not name this variant
PMID 20301399 ↗
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.

Schaefer GB et al. · 2013

Schaefer and Mendelsohn (2013) provide clinical genetics evaluation guidelines for identifying the etiology of autism spectrum disorders. This practice guideline does not discuss the specific variant NM_000548.5:c.3117G>A or any individual gene.
Does not name this variant
PMID 23519317 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Green et al. (2013) present ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. This policy statement on secondary findings does not discuss the specific variant NM_000548.5:c.3117G>A.
Does not name this variant
PMID 23788249 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Kalia SS et al. · 2017

Kalia et al. (2017) present the 2016 update (ACMG SF v2.0) for reporting secondary findings in clinical exome and genome sequencing. This policy statement on secondary findings does not discuss the specific variant NM_000548.5:c.3117G>A.
Does not name this variant
PMID 27854360 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).

Miller DT et al. · 2022

Miller et al. (2022) present the ACMG SF v3.1 list for reporting secondary findings in clinical exome and genome sequencing. This updated policy statement does not discuss the specific variant NM_000548.5:c.3117G>A.
Does not name this variant
PMID 35802134 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Nykamp et al. (2017) presents Sherloc, a comprehensive refinement of the ACMG-AMP variant classification criteria. This methodology paper does not discuss the specific variant NM_000548.5:c.3117G>A.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 25 / 1,612,750 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.090 Open source ↗

ClinVar 5 Likely benign · 2 Benign · 1 Likely Benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 452788)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV113489825, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.