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.1 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.2 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.3 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.4
TSC2
Final classification
VUS
TSC2 c.3884-23C>T · p.?
TSC2
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.
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.
Classification rationale
PM2
BP4
VUS
TSC2 c.3884-23C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_000548.5 · variants mapped to exon structure
TSC2
NM_000548.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: AF=0.058% (121/207686 alleles1 homozygote)
✓
BP4
supporting
Benign
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.
SpliceAI max delta 0.02 — no predicted donor gaindonor lossacceptor gain
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data (with confirmed paternity and maternity) is available for this variant.
PS3
No functional experimental data exists for NM_000548.5:c.3884-23C>T.
PS4
No case-control or affected individual data is available for this variant.
PM1
This deep intronic variant (c.3884-23C>T) does not localize to a known mutational hotspot or critical functional domain.
PM6
No de novo observation (without confirmed paternity and maternity) has been reported for this variant.
PP1
No cosegregation data is available for this variant.
PP3
Multiple lines of computational evidence do NOT support a deleterious effect.
PP4
No patient phenotype or family history data is available for this variant.
PP5
This variant is absent from ClinVar.
Benign
BA1
The overall gnomAD allele frequency of 0.058% (v2.1) is well below the 1% threshold for BA1.
BS1
The overall gnomAD allele frequency of 0.058% (v2.1) is below the 0.3% threshold for BS1.
BS2
Although the variant is observed in gnomAD (121-458 alleles including 1-3 homozygotes), individual-level phenotype confirmation is not available.
BS3
No well-established functional studies demonstrate no damaging effect for this variant.
BS4
No segregation data is available.
BP2
No data on observations in trans with a known pathogenic variant is available.
BP5
No case with an alternate molecular basis for disease has been reported in an individual carrying this variant.
BP6
This variant is absent from ClinVar.
N/A · 9
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.029%
· 458 / 1,566,046
3 hom · FAF 0.0084%
3 hom · FAF 0.0084%
European (Finnish) 333 / 59,276 |
0.56% 3 hom |
Remaining individuals 9 / 60,706 |
0.015% |
European (non-Finnish) 115 / 1,155,936 |
0.0099% |
African/African American 1 / 74,078 |
0.0013% |
+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.058%
· 121 / 207,686
1 hom · FAF 0.011%
1 hom · FAF 0.011%
European (Finnish) 102 / 19,366 |
0.53% 1 hom |
Remaining individuals 3 / 5,818 |
0.052% |
European (non-Finnish) 15 / 88,150 |
0.017% |
Admixed American 1 / 27,100 |
0.0037% |
+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links