TSC2c.4006-8C>TBenign

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Variant interpretation report

TSC2 c.4006-8C>T, p.?

NM_000548.5:c.4006-8C>T NP_000539.2:p.? View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A 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: 2 strong (benign) · 3 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 14 Benign · 5 Likely benign
Pipeline record: 16 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

BS1 (strong): This variant is present in gnomAD at allele frequencies exceeding the expected prevalence of tuberous sclerosis complex. The NFE subpopulation AF is 0.3946% in v2.1 (365/92500 alleles, 4 homozygotes) and 0.4712% in v4.1 (5465/1159748 alleles, 13 homozygotes). TSC has an estimated incidence of ~1:6000 to 1:10000 live births, making the observed population frequency incompatible with a highly penetrant pathogenic variant. Under generic ACMG rules, BS1 applies when AF exceeds the expected disease frequency (>0.3% threshold used here).
BS2 (strong): This variant has been observed in a homozygous state in ostensibly healthy population controls — 5 homozygotes in gnomAD v2.1 and 15 homozygotes in gnomAD v4.1. Tuberous sclerosis complex is an autosomal dominant disorder with near-complete penetrance and significant morbidity. The presence of homozygotes in a general population database is incompatible with a pathogenic role, providing strong evidence for a benign classification.
BP4 (supporting): SpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.00 across acceptor gain, acceptor loss, donor gain, and donor loss). Multiple in silico tools for splice prediction (SpliceAI delta = 0.00) agree that this variant does not alter normal splicing, supporting a benign interpretation.
BP6 (supporting): This variant has been classified as Benign by 14 clinical diagnostic laboratories and as Likely benign by 5 clinical diagnostic laboratories in ClinVar (Variation ID 49281). Multiple independent, reputable clinical testing laboratories have reached a consensus benign interpretation. The ClinVar review status is 'criteria provided, single submitter' for individual submissions, but the aggregate consensus across 19 clinical laboratories provides supporting evidence for a benign classification.
BP7 (supporting): c.4006-8C>T is an intronic variant located at position -8 of exon 34. SpliceAI predicts no impact on splicing (max delta = 0.00), indicating the variant does not affect the splice consensus sequence nor create a cryptic splice site. Under ACMG/AMP guidelines, intronic variants at non-conserved positions with no predicted splicing effect may be classified as BP7 (supporting benign).

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: 5

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 5

BS1Strong

BS1 · strong

This variant is present in gnomAD at allele frequencies exceeding the expected prevalence of tuberous sclerosis complex. The NFE subpopulation AF is 0.3946% in v2.1 (365/92500 alleles, 4 homozygotes) and 0.4712% in v4.1 (5465/1159748 alleles, 13 homozygotes). TSC has an estimated incidence of ~1:6000 to 1:10000 live births, making the observed population frequency incompatible with a highly penetrant pathogenic variant. Under generic ACMG rules, BS1 applies when AF exceeds the expected disease frequency (>0.3% threshold used here).

BS2Strong

BS2 · strong

This variant has been observed in a homozygous state in ostensibly healthy population controls — 5 homozygotes in gnomAD v2.1 and 15 homozygotes in gnomAD v4.1. Tuberous sclerosis complex is an autosomal dominant disorder with near-complete penetrance and significant morbidity. The presence of homozygotes in a general population database is incompatible with a pathogenic role, providing strong evidence for a benign classification.

BP4Supporting

BP4 · supporting

SpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.00 across acceptor gain, acceptor loss, donor gain, and donor loss). Multiple in silico tools for splice prediction (SpliceAI delta = 0.00) agree that this variant does not alter normal splicing, supporting a benign interpretation.

BP6Supporting

BP6 · supporting

This variant has been classified as Benign by 14 clinical diagnostic laboratories and as Likely benign by 5 clinical diagnostic laboratories in ClinVar (Variation ID 49281). Multiple independent, reputable clinical testing laboratories have reached a consensus benign interpretation. The ClinVar review status is 'criteria provided, single submitter' for individual submissions, but the aggregate consensus across 19 clinical laboratories provides supporting evidence for a benign classification.

BP7Supporting

BP7 · supporting

c.4006-8C>T is an intronic variant located at position -8 of exon 34. SpliceAI predicts no impact on splicing (max delta = 0.00), indicating the variant does not affect the splice consensus sequence nor create a cryptic splice site. Under ACMG/AMP guidelines, intronic variants at non-conserved positions with no predicted splicing effect may be classified as BP7 (supporting benign).

Recorded classification: 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, BS2 strong, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 2 strong benign + 3 supporting benign, which maps to 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

6,017 / 1,575,890 alleles

gnomAD v4.1: 6,017 / 1,575,890 alleles. Recorded AF 0.00381816. Recorded homozygote count 15.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00243587; MAF= 0.24359%, 538/220866 alleles, homozygotes = 5) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00394595; MAF= 0.39459%, 365/92500 alleles, homozygotes = 4); grpmax FAF= 0.00380144.

Applied · BS1, BS2 →

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

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

19 reported laboratory submissions

14 Benign · 5 Likely benign.

Applied · BP6 → 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; COSV104573703, n = 2 times).

Context only COSMIC ↗

For specialists

Technical detail

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

27 criteria with recorded statuses: 5 met · 5 not met · 10 not assessed · 7 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 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000548.5:c.4006-8C>T is an intronic variant at position -8 of exon 34 in TSC2, not predicted to alter splicing (SpliceAI delta = 0.00).

This variant is present in gnomAD at appreciable population frequencies: v2.1 AF=0.2436% (538/220866 alleles, 5 homozygotes) and v4.1 AF=0.3818% (6017/1575890 alleles, 15 homozygotes), with the highest subpopulation frequency in the European (non-Finnish) group at 0.3946% (v2.1) and 0.4712% (v4.1). These frequencies far exceed the expected prevalence of tuberous sclerosis complex (estimated incidence ~1:6000 to 1:10000 live births), meeting BS1 (strong benign).

Five homozygotes are observed in gnomAD v2.1 and 15 homozygotes in gnomAD v4.1. TSC is an autosomal dominant disorder with near-complete penetrance and significant morbidity; the presence of homozygotes in a general population database is incompatible with pathogenicity, meeting BS2 (strong benign).

This variant has been classified as Benign by 14 clinical diagnostic laboratories and as Likely benign by 5 clinical laboratories in ClinVar (Variation ID 49281), meeting BP6 (supporting benign).

SpliceAI predicts no splicing impact (max delta = 0.00), and the variant is an intronic substitution at a non-canonical splice position, meeting BP4 and BP7 (each supporting benign).

No variant-specific functional studies, de novo observations, cosegregation data, or case-control studies were identified for this variant. The ClinVar criterion-lead submission (SCV000066333, Tuberous sclerosis database) cited PMID:17304050, but the full text of that publication does not mention NM_000548.5:c.4006-8C>T.

Classification: Likely Benign. Benign evidence includes BS1 (strong), BS2 (strong), BP4 (supporting), BP6 (supporting), and BP7 (supporting). No pathogenic or likely pathogenic criteria are met. Under the ACMG/AMP 2015 combining criteria, ≥2 strong benign criteria → Likely Benign.

Met · 5

BS1 StrongThis variant is present in gnomAD at allele frequencies exceeding the expected prevalence of tuberous sclerosis complex. The NFE subpopulation AF is 0.3946% in v2.1 (365/92500 alleles, 4 homozygotes) and 0.4712% in v4.1 (5465/1159748 alleles, 13 homozygotes). TSC has an estimated incidence of ~1:6000 to 1:10000 live births, making the observed population frequency incompatible with a highly penetrant pathogenic variant. Under generic ACMG rules, BS1 applies when AF exceeds the expected disease frequency (>0.3% threshold used here). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 NFE AF = 0.3946%
exceeds BS1 >0.3% threshold
gnomAD v4.1 NFE AF = 0.4712%
TSC incidence ~1:6000
observed AF is far higher than disease prevalence

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 StrongThis variant has been observed in a homozygous state in ostensibly healthy population controls — 5 homozygotes in gnomAD v2.1 and 15 homozygotes in gnomAD v4.1. Tuberous sclerosis complex is an autosomal dominant disorder with near-complete penetrance and significant morbidity. The presence of homozygotes in a general population database is incompatible with a pathogenic role, providing strong evidence for a benign classification. Details ▾Hide ▴

Evidence considered

5 homozygotes in gnomAD v2.1 (total: 538/220866 alleles)
15 homozygotes in gnomAD v4.1 (total: 6017/1575890 alleles)
TSC is a highly penetrant autosomal dominant disorder
homozygous state would be expected to cause severe or lethal phenotype if pathogenic

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingSpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.00 across acceptor gain, acceptor loss, donor gain, and donor loss). Multiple in silico tools for splice prediction (SpliceAI delta = 0.00) agree that this variant does not alter normal splicing, supporting a benign interpretation. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splice impact predicted)
Variant is at intronic position -8
SpliceAI predicts no cryptic splice site creation or canonical splice site disruption

Sources

spliceai ↗

BP6 SupportingThis variant has been classified as Benign by 14 clinical diagnostic laboratories and as Likely benign by 5 clinical diagnostic laboratories in ClinVar (Variation ID 49281). Multiple independent, reputable clinical testing laboratories have reached a consensus benign interpretation. The ClinVar review status is 'criteria provided, single submitter' for individual submissions, but the aggregate consensus across 19 clinical laboratories provides supporting evidence for a benign classification. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 49281
Benign: 14 clinical laboratories
Likely benign: 5 clinical laboratories
No submitter classifies this variant as pathogenic or likely pathogenic

Sources

clinvar ↗

BP7 Supportingc.4006-8C>T is an intronic variant located at position -8 of exon 34. SpliceAI predicts no impact on splicing (max delta = 0.00), indicating the variant does not affect the splice consensus sequence nor create a cryptic splice site. Under ACMG/AMP guidelines, intronic variants at non-conserved positions with no predicted splicing effect may be classified as BP7 (supporting benign). Details ▾Hide ▴

Evidence considered

Intronic variant at c.4006-8 (non-canonical splice position)
SpliceAI delta = 0.00 confirms no predicted splicing alteration
No evolutionary conservation data suggest functional importance of this nucleotide position

Sources

spliceai ↗

Not met · 5 · evaluated, threshold not reached

PM1 c.4006-8 lies in intron 33, near exon 34. TSC2 has a recognized mutational hotspot spanning exons 25–35 that includes the GAP domain (codons ~1517–1750), but the intronic position at nucleotide -8 does not fall within a known critical functional domain or established mutational hotspot residue. No evidence supports PM1. Details ▾Hide ▴

Evidence considered

Intronic position c.4006-8 is adjacent to but not within a critical functional domain
Exploratory evidence recovery noted gene-level hotspot context but no variant-specific PM1 support

Still missing

Location not confirmed within a critical functional domain

PM2 This variant is present in gnomAD at appreciable frequencies: v2.1 overall AF=0.2436% (538/220866 alleles, 5 homozygotes) with NFE AF=0.3946%; v4.1 overall AF=0.3818% (6017/1575890 alleles, 15 homozygotes) with NFE AF=0.4712%. Under generic ACMG non-VCEP cutoffs, PM2 requires AF <0.1% in all populations. The observed frequencies exceed this threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.2436% (exceeds PM2 <0.1% threshold)
gnomAD v4.1 AF = 0.3818% (exceeds PM2 <0.1% threshold)
5 homozygotes in v2.1
15 homozygotes in v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 In silico tools do not predict a deleterious effect for this variant. SpliceAI predicts no significant splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant — these tools are designed for missense variants. No HCI prior score is available for TSC2. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splice impact predicted)
REVEL not available (intronic variant)
BayesDel not available (intronic variant)
HCI prior not available for TSC2

Sources

spliceai ↗

PP5 PP5 requires a reputable source (e.g., clinical diagnostic laboratory with recognized expertise) to report the variant as pathogenic. ClinVar reports NM_000548.5:c.4006-8C>T as Benign by 14 clinical laboratories and as Likely benign by 5 clinical laboratories (Variation ID 49281). No reputable source classifies this variant as pathogenic. This criterion is not met; instead the ClinVar consensus supports BP6. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 49281: Benign (14 clinical labs)
Likely benign (5 labs)
No clinical laboratory has classified this variant as pathogenic or likely pathogenic

Sources

clinvar ↗

BA1 BA1 requires allele frequency >1% in a general population database. In gnomAD v2.1 the maximum subpopulation AF is 0.3946% (NFE) and in v4.1 it is 0.4712% (NFE). Both are below the 1% threshold. BA1 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpopulation AF = 0.3946% (NFE)
gnomAD v4.1 max subpopulation AF = 0.4712% (NFE)
Both below BA1 >1% threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo occurrence of NM_000548.5:c.4006-8C>T with confirmed paternity has been identified in ClinVar criterion-lead submissions, published literature, or exploratory evidence recovery. Two papers (PMID:15798777, PMID:17304050) flagged for de novo/PS2 theme did not mention this variant in available abstracts or full text. Details ▾Hide ▴

Evidence considered

Exploratory evidence recovery found no de novo observations
PMID:17304050 full text searched
variant not found
PMID:15798777 abstract reviewed
variant not mentioned

Still missing

No de novo occurrence data available for this variant

Sources

1579877717304050

PS3 No functional studies specifically assaying NM_000548.5:c.4006-8C>T (e.g., minigene splicing reporter, RT-PCR, protein function) were identified in literature, ClinVar criterion-lead submissions, or exploratory evidence recovery. Details ▾Hide ▴

Evidence considered

Exploratory evidence recovery found no functional studies for this variant
PMID:25741868 and PMID:26467025 are framework/method papers
not variant-specific functional studies

Still missing

No variant-specific functional assay data available

Sources

2574186826467025

PS4 No case-control studies comparing the prevalence of NM_000548.5:c.4006-8C>T in TSC-affected individuals versus population controls were identified. The variant's presence at appreciable frequency in gnomAD (0.24-0.38%) suggests it is unlikely to be enriched in affected cohorts. Details ▾Hide ▴

Evidence considered

No case-control data available
gnomAD population frequency is inconsistent with a highly penetrant pathogenic variant

Still missing

No case-control or cohort enrichment data

PM6 No de novo occurrence of NM_000548.5:c.4006-8C>T without confirmed paternity/maternity was identified. Papers flagged for PM6 (PMID:15798777, PMID:17304050) did not mention this variant in abstracts or full text. Details ▾Hide ▴

Evidence considered

Exploratory evidence recovery found no de novo observations
PMID:17304050 full text searched
variant not found
PMID:15798777 abstract reviewed
variant not mentioned

Still missing

No de novo observations with or without parental confirmation

Sources

1579877717304050

PP1 No cosegregation data are available for NM_000548.5:c.4006-8C>T in families with tuberous sclerosis complex. No published pedigrees documenting segregation of this variant with disease were identified. Details ▾Hide ▴

Evidence considered

Exploratory evidence recovery found no cosegregation data

Still missing

No family segregation data available

PP4 No patient phenotype or family history data specific to NM_000548.5:c.4006-8C>T were available for review. PP4 requires that the variant be identified in a patient whose phenotype or family history is highly specific for the disease. Details ▾Hide ▴

Evidence considered

No patient-specific phenotypic data available

Still missing

No proband phenotype or family history data

BS3 No variant-specific functional studies demonstrating a benign effect (e.g., normal splicing by RT-PCR, retained protein function) were identified for NM_000548.5:c.4006-8C>T. While SpliceAI predicts no splicing impact (delta=0.00), this alone is insufficient for BS3 without confirmatory in vitro or in vivo functional data. Details ▾Hide ▴

Evidence considered

SpliceAI delta = 0.00 suggests no splice alteration
No confirmatory functional assay (minigene
RT-PCR) available

Still missing

No direct functional assay confirming benign splicing or protein function

Sources

spliceai ↗

BS4 No data are available regarding non-segregation of NM_000548.5:c.4006-8C>T with tuberous sclerosis complex in affected families. BS4 requires observation that the variant does not segregate with disease. Details ▾Hide ▴

Evidence considered

No segregation or non-segregation data available

Still missing

No family segregation data to evaluate BS4

BP2 No observation of NM_000548.5:c.4006-8C>T in trans with a known pathogenic TSC2 variant has been identified. In a dominant disorder such as TSC, observing this variant in trans with a pathogenic variant without a more severe phenotype would support BP2, but no such data are available. Details ▾Hide ▴

Evidence considered

No biallelic/in trans observations available

Still missing

No data on co-occurrence with pathogenic TSC2 variants in trans

BP5 No data are available indicating that NM_000548.5:c.4006-8C>T has been observed in a patient with an alternate molecular basis for tuberous sclerosis complex. BP5 requires that the variant be found in a case with a clear alternate genetic cause of disease. Details ▾Hide ▴

Evidence considered

No data on alternate molecular cause in carriers

Still missing

No observations in cases with alternate molecular diagnoses

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/Ac.4006-8C>T is an intronic substitution at position -8 of exon 34. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable without functional confirmation of a splicing defect. Details ▾Hide ▴

Evidence considered

Intronic variant at position c.4006-8
outside canonical splice consensus (±1
2)
SpliceAI delta score = 0.00 predicts no splicing impact
pvs1_variant_assessment confirms variant bucket is 'other'
apply_generic_pvs1_framework=false

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PS1 N/APS1 applies when the variant produces the same amino acid change as a previously established pathogenic variant. c.4006-8C>T is intronic with no predicted protein consequence (NP_000539.2:p.?); PS1 is not applicable. Details ▾Hide ▴

Evidence considered

Intronic variant with no amino acid change

PM5 N/APM5 requires a novel missense variant at an amino acid residue where a different pathogenic missense has been seen. c.4006-8C>T is an intronic substitution with no predicted amino acid change (NP_000539.2:p.?). PM5 candidates file confirms no residue-level data available for classic PM5 search. Not applicable. Details ▾Hide ▴

Evidence considered

Intronic variant
no amino acid residue change

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common mechanism of disease. c.4006-8C>T is an intronic substitution, not a missense variant. Not applicable. Details ▾Hide ▴

Evidence considered

Intronic variant
PP2 requires a missense variant

BP1 N/ABP1 applies to missense variants in genes where a truncating variant is the primary mechanism of disease and the missense is found in conjunction with a pathogenic truncating variant. c.4006-8C>T is an intronic substitution, not a missense variant. Not applicable. Details ▾Hide ▴

Evidence considered

Intronic variant
BP1 requires a missense variant

BP3 N/ABP3 applies to in-frame indels in repetitive regions. c.4006-8C>T is a single nucleotide substitution, not an indel. Not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is a modified rule for novel missense variants at the same residue as a known pathogenic missense (replacement for PM5 under certain VCEP frameworks). c.4006-8C>T is an intronic substitution, not a missense variant. Not applicable. Details ▾Hide ▴

Evidence considered

Intronic variant
PS5 is only relevant for missense substitutions

Identifiers

Gene: TSC2
Transcript: NM_000548.5
Coding (HGVS c.): NM_000548.5:c.4006-8C>T
Protein (HGVS p.): NP_000539.2:p.?
GRCh38: chr16:2084220 C>T
GRCh37: chr16:2134221 C>T
ClinVar: 49281
COSMIC: COSV104573703

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

	Protein	Location	Classification	Link

gnomAD v4.1 6,017 / 1,575,890 alleles AF 0.00382 · 15 homozygotes · FAF 0.00461

gnomAD v2.1 538 / 220,866 alleles AF 0.00244 · 5 homozygotes · FAF 0.0038

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0.0038 · 6017 / 1,575,890 alleles · 15 hom · FAF 0.0046

European (non-Finnish)5465 / 1,159,748	0.004713 hom
Admixed American201 / 55,630	0.0036
Remaining individuals220 / 60,990	0.00361 hom
African/African American62 / 73,896	0.00084
South Asian50 / 86,804	0.000581 hom
Middle Eastern2 / 6,028	0.00033
European (Finnish)12 / 60,312	0.0002
Ashkenazi Jewish4 / 28,974	0.00014
East Asian1 / 42,596	2.3e-05

0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.0024 · 538 / 220,866 alleles · 5 hom · FAF 0.0038

European (non-Finnish)365 / 92,500	0.00394 hom
Admixed American116 / 30,504	0.00381 hom
Remaining individuals21 / 6,130	0.0034
African/African American17 / 19,760	0.00086
South Asian14 / 25,778	0.00054
European (Finnish)4 / 20,992	0.00019
East Asian1 / 15,960	6.3e-05

0 alternate alleles recorded in 1 other group: Ashkenazi Jewish.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00381816; MAF= 0.38182%, 6017/1575890 alleles, homozygotes = 15) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00471223; MAF= 0.47122%, 5465/1159748 alleles, homozygotes = 13); grpmax FAF= 0.0046076.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.030

Pangolin splice gain

0.040

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 (no splice impact predicted)
Variant is at intronic position -8
SpliceAI predicts no cryptic splice site creation or canonical splice site disruption

Sources

spliceai ↗

Evidence considered

Intronic variant at c.4006-8 (non-canonical splice position)
SpliceAI delta = 0.00 confirms no predicted splicing alteration
No evolutionary conservation data suggest functional importance of this nucleotide position

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00 (no splice impact predicted)
REVEL not available (intronic variant)
BayesDel not available (intronic variant)
HCI prior not available for TSC2

Sources

spliceai ↗

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

Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex.

Reports mutational analysis of TSC1 and TSC2 in 490 patients, identifying pathogenic mutations in 362 (74% detection rate). Describes genotype-phenotype correlations showing TSC2 mutations associate with more severe phenotypes. NM_000548.5:c.4006-8C>T was not mentioned in the abstract or available text.
Does not name this variant
PMID 15798777 ↗
Quoted passage
We identified pathogenic mutations in 362 patients, a mutation detection rate of 74%.
Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

Au KS et al. · 2007

Genotype-phenotype study of 325 individuals with definite TSC, identifying mutations in 72% of de novo and 77% of familial cases. TSC2 mutations associated with more hypomelanotic macules and learning disability. NM_000548.5:c.4006-8C>T was not identified in full text including supplementary material.
Does not name this variant
PMID 17304050 ↗
Quoted passage
We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene.
Full text searched; variant absent from Results, Tables 1-3, and supplementary content.
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.

ACMG/AMP joint consensus guideline for interpretation of sequence variants, establishing the five-tier classification framework (pathogenic, likely pathogenic, VUS, likely benign, benign) and 28 evidence criteria used in clinical variant assessment. Does not discuss NM_000548.5:c.4006-8C>T or any specific TSC2 variant.
Does not name this variant
PMID 25741868 ↗
Quoted passage
This report describes updated standards and guidelines for the classification of sequence variants using criteria informed by expert opinion and empirical data.
Full text searched; variant absent from all sections. This is a methods/framework guideline with no variant-level data.
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Describes a rules-based DNA variant scoring system for pathogenicity assessment applied to over 16,500 assessments on 11,894 variants from 338 genes. Reports interobserver concordance of 98.5% among trained scientists. Does not discuss NM_000548.5:c.4006-8C>T or any specific TSC2 variant.
Does not name this variant
PMID 26467025 ↗
Quoted passage
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign.
Tuberous Sclerosis Complex.

Adam MP et al. · 1993

No paper-specific finding is recorded.

PMID 20301399 ↗
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.

No paper-specific finding is recorded.

PMID 23519317 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Green RC et al. · 2013

No paper-specific finding is recorded.

PMID 23788249 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.

No paper-specific finding is recorded.

PMID 25356965 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

No paper-specific finding is recorded.

PMID 28492532 ↗

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

gnomAD v4.1 6,017 / 1,575,890 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 14 Benign · 5 Likely benign Open source ↗

COSMIC Captured COSMIC 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

ClinVar

This variant has been reported in ClinVar as Benign (14 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 49281)

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; COSV104573703, n = 2 times).