About TSC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC2 c.3884-17C>G, p.?
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.
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
Population frequency is above the default BS1 threshold of 0.3%. In gnomAD v4.1, this variant has an Amish population frequency of 0.65789% (6/912), which exceeds 0.3%, and the variant is also recurrent across gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada.
BP4Supporting
BP4 · supporting
Available computational evidence supports no meaningful splice effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, which argues against an abnormal splicing consequence for this intronic change.
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: BS1 strong benign, BP4 supporting benign; combination = no applied criteria, 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
1,407 / 1,569,834 alleles
gnomAD v4.1: 1,407 / 1,569,834 alleles. Recorded AF 0.000896273. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00061533; MAF= 0.06153%, 131/212894 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00125942; MAF= 0.12594%, 115/91312 alleles, homozygotes = 0); grpmax FAF= 0.00162279.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000434499; MAF= 0.04345%, 8/18412 alleles, homozygotes = 0) and has highest observed frequency in the amr population (AF= 0.00119332; grpmax FAF95= 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
11 reported laboratory submissions
6 Benign · 4 Likely benign · 1 Uncertain significance.
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104375921, n = 2 times).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 12 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The TSC2 NM_000548.5:c.3884-17C>G (NP_000539.2:p.?) variant has been reported in ClinVar predominantly as benign or likely benign, without an expert panel review.
This variant is present in population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with the highest observed frequency of 0.65789% (6/912) in the Amish population in gnomAD v4.1, which is above the default BS1 threshold of 0.3% and below the default BA1 threshold of 1%.
In silico splicing analysis does not support a deleterious effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 2
BS1 StrongPopulation frequency is above the default BS1 threshold of 0.3%. In gnomAD v4.1, this variant has an Amish population frequency of 0.65789% (6/912), which exceeds 0.3%, and the variant is also recurrent across gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 Amish AF 0.00657895 (6/912).
- gnomAD v2.1 total AF 0.00061533 (131/212894).
- gnomAD-Canada total AF 0.000434499 (8/18412).
Sources
BP4 SupportingAvailable computational evidence supports no meaningful splice effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, which argues against an abnormal splicing consequence for this intronic change. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PVS1 TSC2 loss of function is an established disease mechanism, but this intronic variant is at c.3884-17 and is not a canonical +/-1,2 splice-site variant, nonsense variant, or frameshift variant. The generic PVS1 assessment does not place it in a default null-variant category, and no RNA evidence was identified to show a loss-of-function splicing effect. Details ▾Hide ▴
Evidence considered
- Generic PVS1 eligibility for TSC2 is supported at the gene level.
- Variant-level generic PVS1 scaffold does not support automatic PVS1 application.
- SpliceAI shows max delta score 0.00.
Still missing
- RNA or minigene data showing whether this variant alters splicing.
Sources
PM2 Population frequency is not low enough for PM2. In gnomAD v2.1, this variant is present at 0.12594% in the European non-Finnish population, which is above the default PM2 rarity threshold of 0.1%, and it is also present in gnomAD v4.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 NFE AF 0.00125942 (115/91312).
- gnomAD v4.1 total AF 0.000896273 (1407/1569834).
- gnomAD-Canada total AF 0.000434499 (8/18412).
Sources
PP3 Available computational evidence does not support a damaging effect on splicing. SpliceAI predicts no significant splice impact with a max delta score of 0.00, and no REVEL, BayesDel, or HCI prior score was available for this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL not found.
- BayesDel not found.
- HCI prior not available for TSC2.
Sources
BA1 Population frequency does not reach the default BA1 threshold of 1%. The highest observed population frequency was 0.65789% in Amish individuals in gnomAD v4.1, which is below 1%. Details ▾Hide ▴
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar record review did not provide de novo evidence usable for PS2.
Still missing
- Documented proband-parent testing with confirmed de novo status.
Sources
PS3 No well-established functional study was identified showing that this variant damages TSC2 function or causes abnormal splicing. Details ▾Hide ▴
Evidence considered
- No exact-variant functional evidence was retrieved.
Still missing
- Published RNA
- minigene
- or other validated functional assay for the exact variant.
Sources
PS4 No case-control enrichment data or counted series of affected individuals sufficient for PS4 were identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar shows mixed benign/likely benign/VUS submissions but no prevalence evidence for PS4.
Still missing
- Affected-case counts or case-control data for the exact variant.
Sources
PM6 No presumed de novo report with incomplete parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No PM6-usable de novo evidence was retrieved.
Still missing
- A proband report showing absent parental variant status without full confirmation details.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation evidence was retrieved.
Still missing
- Pedigree or co-segregation data in affected relatives.
Sources
PP4 No phenotype-specific evidence was provided to show a highly specific TSC2-related clinical presentation attributable to this variant. Details ▾Hide ▴
Still missing
- Detailed phenotype data with genotype-phenotype specificity.
BS2 No data were identified showing this variant in definitively unaffected individuals at an evidence level sufficient for BS2. Details ▾Hide ▴
Evidence considered
- Population database observations alone were not treated as BS2 evidence.
Still missing
- Unaffected carrier data with appropriate age and penetrance context.
Sources
BS3 No well-established functional study was identified showing normal splicing or preserved TSC2 function for this variant. Details ▾Hide ▴
Evidence considered
- No BS3-qualifying functional study was retrieved.
Still missing
- Published benign functional or RNA evidence for the exact variant.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- Informative family data showing lack of segregation with disease.
BP2 No confirmed co-occurrence with another pathogenic variant in a phase context informative for BP2 was identified. Details ▾Hide ▴
Evidence considered
- No BP2-usable co-occurrence evidence was retrieved.
Still missing
- Cis/trans phase data with another pathogenic variant.
Sources
BP5 No alternate molecular explanation for phenotype was provided that would support BP5. Details ▾Hide ▴
Still missing
- Clinical context showing an independent cause of disease.
BP7 This intronic variant is outside the canonical splice consensus and SpliceAI predicts no significant splice impact, but no direct RNA evidence was identified and the available evidence was not sufficient to apply BP7 confidently in this review. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- No exact-variant RNA validation was identified.
Still missing
- RNA evidence confirming no effect on splicing.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is an intronic variant with no established protein change, so same-amino-acid substitution logic does not apply. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.?
PM1 N/AThis intronic variant is not located in a defined mutational hot spot or critical functional protein domain used for PM1. Details ▾Hide ▴
Evidence considered
- No protein residue/domain consequence is established.
PM3 N/ATSC2-related disease is typically evaluated in an autosomal dominant context, so recessive trans-occurrence evidence is not applicable here. Details ▾Hide ▴
Evidence considered
- Gene-level disease context supports dominant germline disease mechanism.
Sources
pvs1_gene_context
PM4 N/AThis variant does not produce a protein length change such as an in-frame deletion, insertion, or stop-loss. Details ▾Hide ▴
Evidence considered
- Protein consequence is not an in-frame coding change.
PM5 N/APM5 same-residue missense logic does not apply because this is not a missense variant and no residue-based comparator framework was available for use. Details ▾Hide ▴
Evidence considered
- PM5 artifact marked the variant as not eligible for classic same-residue PM5 search.
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this is not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APP5 is not applied because external assertions without independently evaluable evidence are not used as stand-alone support. Details ▾Hide ▴
Evidence considered
- ClinVar assertions were reviewed directly rather than using PP5.
Sources
BP1 N/ABP1 is a missense-specific criterion and does not apply to this intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 is not applicable because this is not an in-frame coding variant in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 is not applied because external assertions without independently evaluable evidence are not used as stand-alone support. Details ▾Hide ▴
Evidence considered
- ClinVar assertions were reviewed directly rather than using BP6.
Sources
Identifiers
- Gene
- TSC2
- Transcript
- NM_000548.5
- Coding (HGVS c.)
- NM_000548.5:c.3884-17C>G
- Protein (HGVS p.)
- NP_000539.2:p.?
- GRCh38
- chr16:2083678 C>G
- GRCh37
- chr16:2133679 C>G
- ClinVar
- 49513
- COSMIC
- COSV104375921
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
1,407 / 1,569,834 alleles
AF 0.000896 · 0 homozygotes · FAF 0.00109
gnomAD v2.1
131 / 212,894 alleles
AF 0.000615 · 0 homozygotes · FAF 0.00162
gnomAD-Canada v1.0
8 / 18,412 alleles
AF 0.000434 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.0009 · 1407 / 1,569,834 alleles · 0 hom · FAF 0.0011
| Amish6 / 912 | 0.0066 |
| European (non-Finnish)1323 / 1,157,912 | 0.0011 |
| Remaining individuals34 / 60,900 | 0.00056 |
| Admixed American22 / 52,862 | 0.00042 |
| European (Finnish)17 / 59,594 | 0.00029 |
| African/African American5 / 74,388 | 6.7e-05 |
0 alternate alleles recorded in 4 other groups: East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00062 · 131 / 212,894 alleles · 0 hom · FAF 0.0016
| European (non-Finnish)115 / 91,312 | 0.0013 |
| European (Finnish)7 / 19,712 | 0.00036 |
| Admixed American8 / 27,468 | 0.00029 |
| Remaining individuals1 / 5,910 | 0.00017 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, East Asian, South Asian.
gnomAD-Canada
AF 0.00043 · 8 / 18,412 alleles · 0 hom
| amr1 / 838 | 0.0012 |
| nfe7 / 11,736 | 0.0006 |
0 alternate alleles recorded in 7 other groups: afr, asj, eas, fin, mid, oth, sas.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000896273; MAF= 0.08963%, 1407/1569834 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00657895; MAF= 0.65789%, 6/912 alleles, homozygotes = 0); grpmax FAF= 0.00109091.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00061533; MAF= 0.06153%, 131/212894 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00125942; MAF= 0.12594%, 115/91312 alleles, homozygotes = 0); grpmax FAF= 0.00162279.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000434499; MAF= 0.04345%, 8/18412 alleles, homozygotes = 0) and has highest observed frequency in the amr population (AF= 0.00119332; grpmax FAF95= 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable computational evidence supports no meaningful splice effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, which argues against an abnormal splicing consequence for this intronic change. Details ▾Hide ▴
PP3 Available computational evidence does not support a damaging effect on splicing. SpliceAI predicts no significant splice impact with a max delta score of 0.00, and no REVEL, BayesDel, or HCI prior score was available for this intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL not found.
- BayesDel not found.
- HCI prior not available for TSC2.
Sources
BP7 This intronic variant is outside the canonical splice consensus and SpliceAI predicts no significant splice impact, but no direct RNA evidence was identified and the available evidence was not sufficient to apply BP7 confidently in this review. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- No exact-variant RNA validation was identified.
Still missing
- RNA evidence confirming no effect on splicing.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 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
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PMID 25741868 ↗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. · 2015No paper-specific finding is recorded.
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PMID 31275557 ↗Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.Shirley BC et al. · 2018No paper-specific finding is recorded.
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PMID 20301399 ↗Tuberous Sclerosis Complex.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 27854360 ↗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. · 2017No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,407 / 1,569,834 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
6 Benign · 4 Likely benign · 1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/49513/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-2133679-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-2083678-C-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-2083678-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000548.5%3Ac.3884…
- OncoKB ↗www.oncokb.org/gene/TSC2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120471408
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= 0.000896273; MAF= 0.08963%, 1407/1569834 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00657895; MAF= 0.65789%, 6/912 alleles, homozygotes = 0); grpmax FAF= 0.00109091.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00061533; MAF= 0.06153%, 131/212894 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00125942; MAF= 0.12594%, 115/91312 alleles, homozygotes = 0); grpmax FAF= 0.00162279.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000434499; MAF= 0.04345%, 8/18412 alleles, homozygotes = 0) and has highest observed frequency in the amr population (AF= 0.00119332; grpmax FAF95= 0).
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 49513)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104375921, n = 2 times).