NM_000455.5:c.388G>T is a nonsense variant predicted to produce a premature termination codon at position 130 (p.Glu130Ter). This null variant in STK11, a gene where loss of function is a well-established mechanism for Peutz-Jeghers syndrome, meets PVS1 at very strong strength under the ClinGen SVI PVS1 decision framework.1 The truncation at codon 130 removes the majority of the protein kinase domain and the entire C-terminal regulatory region of STK11. The kinase domain is a well-characterized critical functional domain essential for LKB1 catalytic activity and tumor suppressor function, satisfying PM1 at moderate strength.2 This variant is absent from gnomAD v4.1 with 0 alleles observed across 1,590,826 alleles, meeting the PM2 threshold of <0.1% population frequency.3 In silico predictions support a deleterious effect: SpliceAI predicts possible splice impact with a max delta score of 0.52 (acceptor loss), and BayesDel predicts a damaging score of 0.65, satisfying PP3 at supporting strength.4 Overall classification: PATHOGENIC. The combination of PVS1 (very strong), PM1 (moderate), PM2 (supporting), and PP3 (supporting) meets the ACMG/AMP 2015 classification threshold for Pathogenic (1 Very Strong + 1 Moderate + >=1 Supporting).5
STK11
Final classification
Pathogenic
STK11 c.388G>T · p.Glu130Ter
STK11
NM_000455.5:c.388G>T is a nonsense variant predicted to produce a premature termination codon at position 130 (p.Glu130Ter). This null variant in STK11, a gene where loss of function is a well-established mechanism for Peutz-Jeghers syndrome, meets PVS1 at very strong strength under the ClinGen SVI PVS1 decision framework.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 very strong + 1 moderate + 2 supporting, which maps to Pathogenic.
Classification rationale
PVS1PM1PM2PP3
Pathogenic
STK11 c.388G>T
PVS1 + PM1 + PM2 + PP3
→
Pathogenic
4
spliceai ↗bayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_000455.5 · variants mapped to exon structure
STK11
NM_000455.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
This variant is a nonsense change (NP_000446.1:p.(Glu130Ter)) predicted to undergo nonsense-mediated decay. STK11 loss of function is an established mechanism for Peutz-Jeghers syndrome. Under the ClinGen SVI PVS1 decision framework (PMC6185798), nonsense variants in genes with an established loss-of-function disease mechanism are assigned PVS1 at very strong strength. The premature termination codon at position 130 lies well upstream of the last exon-exon junction, meeting NMD prediction criteria.
Nonsense variant c.388G>T producing p.(Glu130Ter) in exon 3 of 9STK11 loss of function is an established germline disease mechanism for Peutz-Jeghers syndromePremature termination at codon 130 predicted to trigger NMD under PVS1 decision framework PMC6185798
✓
PM1
moderate
Pathogenic
This variant introduces a premature termination at codon 130 within the protein kinase domain of STK11 (spanning approximately aa49-309). Truncation at this position removes the majority of the kinase domain including subdomains I-XI and the C-terminal regulatory region. The kinase domain of STK11 is a well-characterized critical functional domain essential for LKB1 catalytic activity and tumor suppressor function.
Truncation at codon 130 removes most of the kinase domain (aa130-309) and the entire C-terminal regionThe STK11 kinase domain is a well-established critical functional domain characterized in structural studiesPMID:24652667 demonstrates domain-specific genotype-phenotype correlations in STK11
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 (0/1,590,826 alleles; AF=0.00000%) and absent from gnomAD v2.1. The allele frequency is well below the 0.1% threshold for PM2 application.
gnomAD v4.1: 0/1590826 alleles
✓
PP3
supporting
Pathogenic
In silico tools support a deleterious effect: SpliceAI predicts a possible splice impact with a max delta score of 0.52 (acceptor loss delta 0.52), and BayesDel predicts a damaging effect with a score of 0.65. The SpliceAI prediction reflects potential cryptic splice effects from the nucleotide change beyond the primary nonsense mechanism.
SpliceAI max delta score: 0.52 (acceptor loss = 0.52above the 0.2 threshold)BayesDel score: 0.65 (above typical deleterious threshold of ~0.5)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence of NM_000455.5:c.388G>T has been reported in the available literature or case materials.
PS3
No variant-specific functional data was identified for NM_000455.5:c.388G>T (p.Glu130Ter) in the seven publications reviewed.
PS4
No published case-control or case series data confirming this variant in affected individuals was identified.
PM6
No de novo observation of this variant has been reported.
PP1
No cosegregation data is available for this variant.
PP4
No proband phenotype or family history information is available for assessment.
PP5
The ClinVar entry (variation ID 824343) has a review status of 'criteria provided, single submitter,' which is not a 3-star expert panel review.
Benign
BA1
This variant is absent from gnomAD (0/1,590,826 alleles; AF=0.0).
BS1
This variant is absent from gnomAD (0/1,590,826 alleles; AF=0.0).
BS2
This variant is absent from all population databases.
BS3
No well-established functional studies demonstrate no deleterious effect for this variant.
BS4
No cosegregation data is available demonstrating lack of segregation with disease.
BP2
No observation of this variant in trans with a known pathogenic STK11 variant has been reported.
BP4
Multiple lines of computational evidence suggest a deleterious effect rather than a benign one.
BP5
No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6
The ClinVar classification for this variant is Pathogenic/Likely pathogenic, not benign.
N/A · 8
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1590826 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74650 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,590,826
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 824343)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.52). BayesDel score = 0.65.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58826710, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
19892943 ↗
Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation.
ONCOKB
24652667 ↗
STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.
ONCOKB
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.
CLINVAR