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TSC2c.2356-15T>AUncertain significance
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Variant interpretation report

TSC2 c.2356-15T>A, p.?

NM_000548.5:c.2356-15T>A NP_000539.2:p.? View identifiers
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.

About TSC2

No gene-level summary was recorded for this case.

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

The variant is rare in population databases by the default non-VCEP rarity threshold used here. In gnomAD v2.1 the total AF is 0.01435% (40/278790; no homozygotes) with highest observed AMR AF 0.09323%, and in gnomAD v4.1 the total AF is 0.00571% (92/1610442; no homozygotes) with grpmax FAF 0.00070689.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational splicing predictors support no significant impact on splicing. SpliceAI shows a maximal delta score of 0.14, and Pangolin scores are low.

Recorded classification: Uncertain significance

Generic ACMG/AMP 2015 final-classification combination rules were used because no official ClinGen/VCEP or local custom gene-specific final-classification framework was available; the retrieved final-classification framework explicitly indicates generic ACMG fallback.

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
92 / 1,610,442 alleles

gnomAD v4.1: 92 / 1,610,442 alleles. Recorded AF 5.71272e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000143477; MAF= 0.01435%, 40/278790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000932256; MAF= 0.09323%, 33/35398 alleles, homozygotes = 0); grpmax FAF= 0.00067374.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
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
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
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 · 5 not met · 15 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The TSC2 c.2356-15T>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where aggregate submissions include Benign, Likely benign, and Uncertain significance classifications.

The variant is present at low frequency in population databases, with gnomAD v2.1 total AF 0.01435% (40/278790 alleles) and gnomAD v4.1 total AF 0.00571% (92/1610442 alleles), with no homozygotes reported.

In silico splicing prediction is consistent with no significant splice effect, with SpliceAI maximal delta score 0.14.

Met · 2

PM2 SupportingThe variant is rare in population databases by the default non-VCEP rarity threshold used here. In gnomAD v2.1 the total AF is 0.01435% (40/278790; no homozygotes) with highest observed AMR AF 0.09323%, and in gnomAD v4.1 the total AF is 0.00571% (92/1610442; no homozygotes) with grpmax FAF 0.00070689. Details ▾Hide ▴
Rule
Default non-VCEP rarity threshold applied in this review: PM2 when population frequency remains below 0.1% across reviewed gnomAD datasets.
Evidence considered
  • gnomAD v2.1 total AF 0.000143477; AMR AF 0.000932256; 0 homozygotes
  • gnomAD v4.1 total AF 0.0000571272; grpmax FAF 0.00070689; 0 homozygotes
Still missing
  • No gene-specific population threshold was available in the reviewed materials.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational splicing predictors support no significant impact on splicing. SpliceAI shows a maximal delta score of 0.14, and Pangolin scores are low. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP4 for multiple lines of computational evidence supporting no impact on gene or gene product.
Evidence considered
  • SpliceAI max delta score 0.14
  • Pangolin SG 0.02 and SL -0.03
Still missing
  • Experimental RNA data would further confirm the predicted absence of splicing impact.
Sources
spliceai ↗

Not met · 5 · evaluated, threshold not reached

PVS1 NM_000548.5:c.2356-15T>A is a noncanonical intronic variant at position -15, not a predicted null variant under generic ACMG PVS1. SpliceAI shows a low maximal delta score of 0.14, which does not support a loss-of-function splicing effect. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PVS1 for predicted null variants in a gene where loss of function is a known disease mechanism.
Evidence considered
  • Variant location c.2356-15T>A
  • SpliceAI max delta score 0.14
Still missing
  • RNA studies demonstrating aberrant splicing were not identified.
  • A gene-specific or ClinGen PVS1 decision tree for this variant was not available.
Sources
spliceai ↗PMID:25741868 ↗25741868
PM1 No mutational hot spot or well-established critical functional domain evidence was identified for this intronic position. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PM1.
Evidence considered
  • Intronic location c.2356-15
Still missing
  • Domain-specific or hotspot evidence would be needed.
PP3 Available computational splicing evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with maximal delta score 0.14. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP3.
Evidence considered
  • SpliceAI DS_AG 0.14, DS_AL 0.00, DS_DG 0.01, DS_DL 0.02
  • Pangolin SG 0.02, SL -0.03
Still missing
  • Additional in silico or RNA data would be needed to support a deleterious splicing effect.
Sources
spliceai ↗
BA1 The allele frequency does not meet the benign stand-alone threshold used here. The highest robust frequencies in the reviewed gnomAD datasets are below 1%. Details ▾Hide ▴
Rule
Default non-VCEP benign stand-alone threshold applied in this review: BA1 when population frequency exceeds 1%.
Evidence considered
  • gnomAD v2.1 AMR AF 0.09323%
  • gnomAD v4.1 AMR AF 0.09497%; total AF 0.00571%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The allele frequency does not exceed the benign strong threshold used here. The highest robust frequencies in the reviewed gnomAD datasets remain below 0.3%. Details ▾Hide ▴
Rule
Default non-VCEP benign strong threshold applied in this review: BS1 when population frequency exceeds 0.3%.
Evidence considered
  • gnomAD v2.1 AMR AF 0.09323%
  • gnomAD v4.1 AMR AF 0.09497%
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 15 · no assessment recorded

PS2 No confirmed de novo data with maternity and paternity confirmation were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PS2.
Still missing
  • Trio testing or a documented de novo report would be needed.
PS3 No well-established functional studies showing a damaging effect were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PS3.
Still missing
  • Validated RNA or other functional assay data would be needed.
Sources
PMID:25741868 ↗25741868
PS4 No case-control enrichment or statistically increased prevalence in affected individuals was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PS4.
Evidence considered
  • ClinVar aggregate submissions without case-control enrichment data
Still missing
  • Case series, cohort enrichment, or formal case-control data would be needed.
Sources
clinvar ↗
PM3 No recessive trans observations were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PM3.
Still missing
  • Phase-confirmed trans observations in a recessive context would be needed.
PM6 No assumed de novo data without full parental confirmation were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PM6.
Still missing
  • A reported de novo occurrence without complete parental confirmation would be needed.
PP1 No segregation data were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP1.
Still missing
  • Family segregation evidence would be needed.
PP4 No phenotype-specific evidence for a highly specific TSC2-associated presentation was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP4.
Still missing
  • Detailed phenotype and clinical correlation would be needed.
PP5 ClinVar contains mixed submitter classifications and no expert panel assertion. A qualifying pathogenic assertion from a reputable source without accessible primary data was not established. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP5.
Evidence considered
  • ClinVar aggregate classifications: Benign, Likely benign, and Uncertain significance
Still missing
  • A clear reputable-source pathogenic classification would be needed if this criterion were to be considered.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a way that satisfies BS2. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BS2.
Evidence considered
  • No homozygotes reported in gnomAD v2.1 or v4.1
Still missing
  • Well-documented unaffected carrier observations would be needed.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies showing no damaging effect were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BS3.
Still missing
  • Validated RNA or other benign functional assay data would be needed.
Sources
PMID:25741868 ↗25741868
BS4 No segregation evidence showing lack of segregation with disease was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BS4.
Still missing
  • Family nonsegregation data would be needed.
BP2 No phase data demonstrating the variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, were identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP2.
Still missing
  • Phasing data would be needed.
BP5 No alternate molecular basis explaining disease while rendering this variant incidental was identified. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP5.
Still missing
  • An established alternate cause of disease would be needed.
BP6 ClinVar shows mixed submitter classifications and no expert panel review. A qualifying benign assertion from a reputable source without accessible primary data was not established. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP6.
Evidence considered
  • ClinVar summary Benign with single-submitter review status and mixed submitter classifications
Still missing
  • A clear reputable-source benign classification would be needed if this criterion were to be considered.
Sources
clinvar ↗
BP7 The variant is noncanonical intronic and computational splicing evidence argues against splice disruption, but the reviewed materials did not provide additional evidence needed to support BP7 confidently under a strict generic ACMG approach. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP7.
Evidence considered
  • Intronic position c.2356-15T>A
  • SpliceAI max delta score 0.14
Still missing
  • Additional supporting evidence such as conservation or a validated framework explicitly extending BP7 to this intronic context would be needed.
Sources
spliceai ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is a same-amino-acid criterion for protein-altering variants and is not applicable to this intronic variant with no established amino-acid change. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PS1.
Evidence considered
  • Predicted protein consequence p.?
Sources
PMID:25741868 ↗25741868
PM4 N/APM4 addresses protein length changes and is not applicable to this intronic variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PM4.
Evidence considered
  • Intronic variant with predicted protein consequence p.?
Sources
PMID:25741868 ↗25741868
PM5 N/APM5 applies to a novel missense change at a residue with a different pathogenic missense change and is not applicable to this intronic variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PM5.
Evidence considered
  • Intronic variant
Sources
PMID:25741868 ↗25741868
PP2 N/APP2 is a missense-specific criterion and is not applicable to this intronic variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP2.
Evidence considered
  • Intronic variant
Sources
PMID:25741868 ↗25741868
BP1 N/ABP1 is a missense-specific criterion and is not applicable to this intronic variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP1.
Evidence considered
  • Intronic variant
Sources
PMID:25741868 ↗25741868
BP3 N/ABP3 addresses in-frame indels in repetitive regions and is not applicable to this intronic single-nucleotide variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP3.
Evidence considered
  • Intronic SNV
Sources
PMID:25741868 ↗25741868

Identifiers

Gene
TSC2
Transcript
NM_000548.5
Coding (HGVS c.)
NM_000548.5:c.2356-15T>A
Protein (HGVS p.)
NP_000539.2:p.?
GRCh38
chr16:2074185 T>A
GRCh37
chr16:2124186 T>A

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…
gnomAD v4.1 92 / 1,610,442 alleles AF 5.71e-05 · 0 homozygotes · FAF 0.000707
gnomAD v2.1 40 / 278,790 alleles AF 0.000143 · 0 homozygotes · FAF 0.000674

By genetic ancestry

gnomAD v4.1

AF 5.7e-05 · 92 / 1,610,442 alleles · 0 hom · FAF 0.00071
HGDP:BASQUE1 / 44 0.023
1KG:CLM1 / 188 0.0053
Admixed American57 / 60,016 0.00095
HGDP:XY1 / 1,122 0.00089
1KG:XX1 / 2,476 0.0004
Remaining individuals6 / 62,308 9.6e-05
African/African American3 / 74,996 4e-05
European (non-Finnish)26 / 1,179,812 2.2e-05
0 alternate alleles recorded in 86 other groups: European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, Amish, HGDP:JAPANESE, HGDP:ADYGEI, HGDP:ORCADIAN, HGDP:BANTUSOUTHAFRICA, HGDP:YAKUT, HGDP:HAN, HGDP:UYGUR, HGDP:BALOCHI, HGDP:BEDOUIN, HGDP:RUSSIAN, HGDP:DAUR, HGDP:PIMA, HGDP:HEZHEN, HGDP:BIAKA, HGDP:MIAO, HGDP:SINDHI, HGDP:NORTHERNHAN, HGDP:OROQEN, HGDP:SAN, HGDP:TU, HGDP:TUSCAN, HGDP:MBUTI, HGDP:PALESTINIAN, HGDP:TUJIA, HGDP:DRUZE, HGDP:PATHAN, HGDP:MAKRANI, HGDP:BURUSHO, HGDP:MONGOLIAN, HGDP:BOUGAINVILLE, HGDP:PAPUANSEPIK, HGDP:YI, HGDP:NAXI, HGDP:LAHU, HGDP:SARDINIAN, HGDP:KARITIANA, HGDP:MOZABITE, HGDP:YORUBA, HGDP:DAI, HGDP:BERGAMOITALIAN, HGDP:CAMBODIAN, HGDP:FRENCH, HGDP:MANDENKA, HGDP:SURUI, HGDP:BRAHUI, HGDP:HAZARA, HGDP:KALASH, HGDP:PAPUANHIGHLANDS, HGDP:XIBO, HGDP:COLOMBIAN, HGDP:BANTUKENYA, HGDP:SHE, HGDP:MAYA, HGDP:XX, 1KG:ESN, 1KG:PUR, 1KG:PJL, 1KG:JPT, 1KG:CHB, 1KG:STU, 1KG:ITU, 1KG:TSI, 1KG:MXL, 1KG:CEU, 1KG:MSL, 1KG:BEB, 1KG:YRI, 1KG:FIN, 1KG:KHV, 1KG:CDX, 1KG:LWK, 1KG:ACB, 1KG:ASW, 1KG:IBS, 1KG:GBR, 1KG:PEL, 1KG:GIH, 1KG:CHS, 1KG:GWD, 1KG:XY.

gnomAD v2.1

AF 0.00014 · 40 / 278,790 alleles · 0 hom · FAF 0.00067
Admixed American33 / 35,398 0.00093
Remaining individuals3 / 7,172 0.00042
European (non-Finnish)4 / 126,084 3.2e-05
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.71272e-05; MAF= 0.00571%, 92/1610442 alleles, homozygotes = 0) and has highest observed frequency in the HGDP:BASQUE population (AF= 0.0227273; MAF= 2.27273%, 1/44 alleles, homozygotes = 0); grpmax FAF= 0.00070689.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000143477; MAF= 0.01435%, 40/278790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000932256; MAF= 0.09323%, 33/35398 alleles, homozygotes = 0); grpmax FAF= 0.00067374.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational splicing predictors support no significant impact on splicing. SpliceAI shows a maximal delta score of 0.14, and Pangolin scores are low. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP4 for multiple lines of computational evidence supporting no impact on gene or gene product.
Evidence considered
  • SpliceAI max delta score 0.14
  • Pangolin SG 0.02 and SL -0.03
Still missing
  • Experimental RNA data would further confirm the predicted absence of splicing impact.
Sources
spliceai ↗
PP3 Available computational splicing evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with maximal delta score 0.14. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 PP3.
Evidence considered
  • SpliceAI DS_AG 0.14, DS_AL 0.00, DS_DG 0.01, DS_DL 0.02
  • Pangolin SG 0.02, SL -0.03
Still missing
  • Additional in silico or RNA data would be needed to support a deleterious splicing effect.
Sources
spliceai ↗
BP7 The variant is noncanonical intronic and computational splicing evidence argues against splice disruption, but the reviewed materials did not provide additional evidence needed to support BP7 confidently under a strict generic ACMG approach. Details ▾Hide ▴
Rule
Generic ACMG/AMP 2015 BP7.
Evidence considered
  • Intronic position c.2356-15T>A
  • SpliceAI max delta score 0.14
Still missing
  • Additional supporting evidence such as conservation or a validated framework explicitly extending BP7 to this intronic context would be needed.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

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 92 / 1,610,442 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record

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

This variant is present in gnomAD v4.1 (AF= 5.71272e-05; MAF= 0.00571%, 92/1610442 alleles, homozygotes = 0) and has highest observed frequency in the HGDP:BASQUE population (AF= 0.0227273; MAF= 2.27273%, 1/44 alleles, homozygotes = 0); grpmax FAF= 0.00070689.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000143477; MAF= 0.01435%, 40/278790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000932256; MAF= 0.09323%, 33/35398 alleles, homozygotes = 0); grpmax FAF= 0.00067374.

ClinVar

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

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).