About TSC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC2 c.3884-23C>T, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from ClinVar and present in gnomAD at very low frequency in the overall population (AF 0.058% in v2.1, 0.029% in v4.1), below the 0.1% threshold for PM2. Grpmax FAF is 0.0105%. Note: 1 homozygote is observed in gnomAD v2.1 and 3 homozygotes in v4.1, concentrated in the Finnish subpopulation (Finnish AF 0.527%), which is unusual for an autosomal dominant tumor suppressor gene but does not negate the low overall population frequency.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no splice impact (max delta score 0.02), which is well below the 0.1 threshold for any splice-altering prediction category. While REVEL and BayesDel are not available for this intronic variant, the available computational evidence supports a benign interpretation with no predicted effect on splicing.
Recorded classification: Uncertain significance
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
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
458 / 1,566,046 alleles
gnomAD v4.1: 458 / 1,566,046 alleles. Recorded AF 0.000292456. Recorded homozygote count 3.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058261; MAF= 0.05826%, 121/207686 alleles, homozygotes = 1) and has highest observed frequency in the European (Finnish) population (AF= 0.00526696; MAF= 0.52670%, 102/19366 alleles, homozygotes = 1); grpmax FAF= 0.0001054.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000548.5:c.3884-23C>T is a deep intronic variant in TSC2 located 23 bases upstream of exon 32. SpliceAI predicts no splice impact (max delta score 0.02), suggesting the variant does not alter normal splicing.
This variant is absent from ClinVar and is present in gnomAD at very low overall frequency (AF 0.058% in v2.1, 0.029% in v4.1), meeting PM2 at supporting strength.
SpliceAI predicts no splice impact (max delta 0.02), meeting BP4 at supporting strength. No other in silico tools (REVEL, BayesDel) are applicable to this intronic variant.
No functional studies, clinical reports, segregation data, or de novo observations are available for this variant. No publications were identified through comprehensive literature screening.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from ClinVar and present in gnomAD at very low frequency in the overall population (AF 0.058% in v2.1, 0.029% in v4.1), below the 0.1% threshold for PM2. Grpmax FAF is 0.0105%. Note: 1 homozygote is observed in gnomAD v2.1 and 3 homozygotes in v4.1, concentrated in the Finnish subpopulation (Finnish AF 0.527%), which is unusual for an autosomal dominant tumor suppressor gene but does not negate the low overall population frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.058% (121/207
- 686 alleles
- 1 homozygote)
- grpmax FAF=0.0105%
- gnomAD v4.1: AF=0.029% (458/1
- 566
- 046 alleles
- 3 homozygotes)
- grpmax FAF=0.0084%
- Absent from ClinVar
Sources
BP4 SupportingSpliceAI predicts no splice impact (max delta score 0.02), which is well below the 0.1 threshold for any splice-altering prediction category. While REVEL and BayesDel are not available for this intronic variant, the available computational evidence supports a benign interpretation with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- All four SpliceAI delta scores are null (no prediction above threshold)
- REVEL and BayesDel not applicable (intronic variant with no amino acid change)
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo occurrence data (with confirmed paternity and maternity) is available for this variant. No publications or clinical reports document a de novo observation of NM_000548.5:c.3884-23C>T. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in literature or clinical databases
Still missing
- De novo testing data unavailable
PS3 No functional experimental data exists for NM_000548.5:c.3884-23C>T. No publications were identified through literature search. SpliceAI predicts no splice impact (max delta 0.02), but this is in silico prediction, not experimental functional evidence suitable for PS3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — no predicted splice impact
- but this is in silico only
- No experimental functional studies found in literature (0 PMIDs screened)
Still missing
- No functional studies available for this variant
Sources
PS4 No case-control or affected individual data is available for this variant. The variant is observed in gnomAD at low frequency but no clinical cohort enrichment data has been reported. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD at low frequency (AF 0.058% v2.1
- 0.029% v4.1)
- No affected-individual cohort data available
Still missing
- No clinical case data available
Sources
PM1 This deep intronic variant (c.3884-23C>T) does not localize to a known mutational hotspot or critical functional domain. Cancerhotspots.org does not list this variant or position as significant. SpliceAI predicts no splice alteration (max delta 0.02), arguing against a functionally critical intronic regulatory position. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue_significant=false
- exact_variant_listed=no
- SpliceAI max delta 0.02 — no evidence of a functionally critical splice regulatory element at this position
- Variant is 23 bp upstream of exon 32
- not in a characterized functional domain
Sources
PM6 No de novo observation (without confirmed paternity and maternity) has been reported for this variant. PM6 requires at least one de novo report in a patient with disease and no family history. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in literature (0 PMIDs screened)
Still missing
- De novo data unavailable
PP1 No cosegregation data is available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data available in literature or databases
Still missing
- Family study data unavailable
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.02, well below the 0.1 threshold for any prediction). REVEL and BayesDel scores are not available for this intronic variant. No in silico tool predicts a damaging consequence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- REVEL: not available (intronic variant
- no amino acid change)
- BayesDel: not available (intronic variant)
- HCI prior: not available (gene not supported)
Sources
PP4 No patient phenotype or family history data is available for this variant. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No patient-level phenotypic data available
Still missing
- Patient phenotype data unavailable
PP5 This variant is absent from ClinVar. No reputable source, including expert panels, has classified NM_000548.5:c.3884-23C>T as pathogenic. The PP5 criterion requires a reputable source to have reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no classification
- no submissions
- no expert panel review
Sources
BA1 The overall gnomAD allele frequency of 0.058% (v2.1) is well below the 1% threshold for BA1. This variant is not common enough in the general population to be considered a benign polymorphism under BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.058% (<1% threshold)
- gnomAD v4.1 overall AF=0.029% (<1% threshold)
Sources
BS1 The overall gnomAD allele frequency of 0.058% (v2.1) is below the 0.3% threshold for BS1. While the Finnish subpopulation frequency is 0.527%, the grpmax FAF (0.0105%) and overall frequency are the primary metrics used for BS1 and both fall below the threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF=0.058% (<0.3% threshold)
- grpmax FAF=0.0105%
- gnomAD v4.1 overall AF=0.029% (<0.3% threshold)
- grpmax FAF=0.0084%
- Finnish subpopulation AF=0.527% but grpmax FAF filters for population stratification bias
Sources
BS2 Although the variant is observed in gnomAD (121-458 alleles including 1-3 homozygotes), individual-level phenotype confirmation is not available. The presence of homozygotes in a population database for an autosomal dominant tumor suppressor gene (TSC2) is notable, but BS2 requires confirmed observation in a healthy adult with full penetrance expected at an early age, which cannot be established from gnomAD alone. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 121 alleles
- 1 homozygote
- gnomAD v4.1: 458 alleles
- 3 homozygotes
- No individual-level phenotype confirmation available from gnomAD
Still missing
- Individual-level phenotype data needed to confirm healthy adult observation
Sources
BS3 No well-established functional studies demonstrate no damaging effect for this variant. SpliceAI prediction of no splice impact (max delta 0.02) is in silico evidence only and does not constitute the well-established experimental functional data required for BS3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — in silico only
- not experimental functional evidence
- No experimental functional studies in literature (0 PMIDs)
Still missing
- No experimental functional data available
Sources
BS4 No segregation data is available. BS4 requires lack of cosegregation with disease in affected family members, and no family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- Family segregation data unavailable
BP2 No data on observations in trans with a known pathogenic variant is available. BP2 requires the variant to be observed in trans with a pathogenic variant in a gene associated with a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans-phase observation data available
Still missing
- Phase data with known pathogenic TSC2 variants unavailable
BP5 No case with an alternate molecular basis for disease has been reported in an individual carrying this variant. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with another explanatory molecular diagnosis
Still missing
- No alternate-molecular-basis data available
BP6 This variant is absent from ClinVar. No reputable source, including expert panels, has classified NM_000548.5:c.3884-23C>T as benign. The BP6 criterion requires a reputable source to have reported the variant as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no classification
- no submissions
- no expert panel review
Sources
PS5 This variant has not been reported in any individual with TSC2-related disease. No clinical publications or database submissions identify NM_000548.5:c.3884-23C>T in an affected proband. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar — no submitter has reported this variant in a disease context
- No publications identified (0 PMIDs)
Still missing
- No proband data available
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a deep intronic variant (c.3884-23C>T, 23 bases upstream of exon 32) that does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application. The PVS1 variant assessment explicitly confirms generic PVS1 framework is not eligible. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.3884-23C>T)
- not a null variant
- PVS1 variant assessment: apply_generic_pvs1_framework=false
- variant_bucket=other
- Gene-level PVS1 gate: eligible (TSC2 LoF mechanism supported)
- but variant-level assessment fails
Sources
PS1 N/AThis is an intronic variant with no protein-level amino acid consequence. PS1 requires the same amino acid change as an established pathogenic variant, which cannot be determined for an intronic substitution. Details ▾Hide ▴
Evidence considered
- Intronic variant c.3884-23C>T has no protein consequence (NP_000539.2:p.?)
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. TSC2 is an autosomal dominant disorder. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants. This is a substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThis is an intronic variant with no amino acid change. PM5 requires a different missense change at the same residue as a known pathogenic missense variant. The PM5 candidate assessment was unable to parse residue context from the intronic variant, and the automated pipeline confirmed PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- PM5 candidates: eligible_for_classic_pm5_search=false
- residue position=null
- Intronic variant — no protein residue context available
Sources
pm5_candidates
PP2 N/AThis is an intronic substitution, not a missense variant. PP2 applies specifically to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.3884-23C>T)
- not missense
BP1 N/AThis is an intronic substitution, not a missense variant. BP1 applies specifically to missense variants in genes where only truncating variants are known to cause disease. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.3884-23C>T)
- not missense
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is an intronic variant (c.3884-23C>T), not a synonymous (silent) variant. BP7 applies specifically to synonymous variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not synonymous/exonic
Identifiers
- Gene
- TSC2
- Transcript
- NM_000548.5
- Coding (HGVS c.)
- NM_000548.5:c.3884-23C>T
- Protein (HGVS p.)
- NP_000539.2:p.?
- GRCh38
- chr16:2083672 C>T
- GRCh37
- chr16:2133673 C>T
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
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TSC2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
458 / 1,566,046 alleles
AF 0.000292 · 3 homozygotes · FAF 8.43e-05
gnomAD v2.1
121 / 207,686 alleles
AF 0.000583 · 1 homozygotes · FAF 0.000105
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00029 · 458 / 1,566,046 alleles · 3 hom · FAF 8.4e-05
| European (Finnish)333 / 59,276 | 0.00563 hom |
| Remaining individuals9 / 60,706 | 0.00015 |
| European (non-Finnish)115 / 1,155,936 | 9.9e-05 |
| African/African American1 / 74,078 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00058 · 121 / 207,686 alleles · 1 hom · FAF 0.00011
| European (Finnish)102 / 19,366 | 0.00531 hom |
| Remaining individuals3 / 5,818 | 0.00052 |
| European (non-Finnish)15 / 88,150 | 0.00017 |
| Admixed American1 / 27,100 | 3.7e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, East Asian, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000292456; MAF= 0.02925%, 458/1566046 alleles, homozygotes = 3) and has highest observed frequency in the European (Finnish) population (AF= 0.00561779; MAF= 0.56178%, 333/59276 alleles, homozygotes = 3); grpmax FAF= 8.43e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058261; MAF= 0.05826%, 121/207686 alleles, homozygotes = 1) and has highest observed frequency in the European (Finnish) population (AF= 0.00526696; MAF= 0.52670%, 102/19366 alleles, homozygotes = 1); grpmax FAF= 0.0001054.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splice impact (max delta score 0.02), which is well below the 0.1 threshold for any splice-altering prediction category. While REVEL and BayesDel are not available for this intronic variant, the available computational evidence supports a benign interpretation with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- All four SpliceAI delta scores are null (no prediction above threshold)
- REVEL and BayesDel not applicable (intronic variant with no amino acid change)
Sources
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.02, well below the 0.1 threshold for any prediction). REVEL and BayesDel scores are not available for this intronic variant. No in silico tool predicts a damaging consequence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 — no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- REVEL: not available (intronic variant
- no amino acid change)
- BayesDel: not available (intronic variant)
- HCI prior: not available (gene not supported)
Sources
BP7 N/AThis is an intronic variant (c.3884-23C>T), not a synonymous (silent) variant. BP7 applies specifically to synonymous variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. Details ▾Hide ▴
Evidence considered
- Variant is intronic
- not synonymous/exonic
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
458 / 1,566,046 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000548.5%3Ac.3884-23C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-2133673-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-2083672-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-2083672-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000548.5%3Ac.3884…
- OncoKB ↗www.oncokb.org/gene/TSC2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TSC2+c.3884-23C%3ET
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000292456; MAF= 0.02925%, 458/1566046 alleles, homozygotes = 3) and has highest observed frequency in the European (Finnish) population (AF= 0.00561779; MAF= 0.56178%, 333/59276 alleles, homozygotes = 3); grpmax FAF= 8.43e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00058261; MAF= 0.05826%, 121/207686 alleles, homozygotes = 1) and has highest observed frequency in the European (Finnish) population (AF= 0.00526696; MAF= 0.52670%, 102/19366 alleles, homozygotes = 1); grpmax FAF= 0.0001054.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).