Classification rationale

PM2 BP4 VUS

STK11 c.*16+7C>T

The STK11 c.*16+7C>T (p.?) variant has been reported in ClinVar as likely benign by two clinical laboratories, and no expert-panel review was identified.¹ This variant is present at low frequency in gnomAD, with AF 0.00639% in v2.1 and AF 0.00677% in v4.1; these values remain below the 0.1% PM2 threshold.² In silico splice prediction does not support a damaging effect, with SpliceAI showing a maximum delta score of 0.01, consistent with no significant splice impact.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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.

Gene diagram · NM_000455.5 · variants mapped to exon structure

STK11 NM_000455.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is rare in population databases, with gnomAD v2.1 AF 0.00639% (8/125122) and gnomAD v4.1 AF 0.00677% (101/1490806), both below the 0.1% PM2 threshold.

gnomAD v2.1 total AF 6.39376e-05.gnomAD v4.1 total AF 6.77486e-05.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Available computational evidence supports no significant impact on splicing. SpliceAI predicts a maximum delta score of 0.01, which is below commonly used splice-impact thresholds; REVEL and BayesDel scores were not available for this noncoding change.

SpliceAI DS_AG 0.0DS_AL 0.0DS_DG 0.01

spliceai ↗

Assessed · not applied · 5 not met · 14 not assessed

Pathogenic

PVS1 STK11 loss of function is an established disease mechanism, but this variant is a noncanonical c.*16+7C>T change in the terminal noncoding region and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.

PS2 No confirmed de novo occurrence with parental testing was identified for this variant.

PS3 No published functional or RNA study was identified showing that this variant damages STK11 function or splicing.

PS4 No enrichment data or series of affected individuals carrying this variant were identified.

PM1 This variant lies in the terminal noncoding region, and no evidence was identified that this position is a mutational hotspot or a well-established critical noncoding element with little benign variation.

PM6 No probable de novo occurrence was identified for this variant.

PP1 No segregation data were identified showing that this variant tracks with disease in a family.

PP3 Available computational evidence does not support a damaging splice effect.

PP4 No case-specific phenotype information was identified to determine whether the clinical presentation is highly specific for an STK11-related disorder.

PP5 No independent reputable-source pathogenic assertion suitable for PP5 use was identified.

Benign

BA1 The population frequency does not meet the BA1 threshold.

BS1 The population frequency does not meet the BS1 threshold.

BS2 Population data show heterozygous carriers but no evidence was identified demonstrating observation in healthy adults at a level sufficient for BS2.

BS3 No well-established functional or RNA study was identified showing that this variant has no damaging effect on STK11 function or splicing.

BS4 No nonsegregation data were identified for this variant.

BP2 No phase or co-occurrence data were identified for this variant.

BP3 No evidence was identified that this variant lies within a repetitive region or a region without known function where small variation is common.

BP5 No evidence was identified for an alternate molecular explanation that would make this variant noncontributory to the phenotype.

BP6 ClinVar reports this variant as likely benign, but no independent reputable-source benign assertion without accessible evidence was identified for BP6 use.

N/A · 7 PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.77486e-05; MAF= 0.00677%, 101/1490806 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.26896e-05; MAF= 0.00827%, 93/1124688 alleles, homozygotes = 0); grpmax FAF= 6.881e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.39376e-05; MAF= 0.00639%, 8/125122 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000145709; MAF= 0.01457%, 2/13726 alleles, homozygotes = 0); grpmax FAF= 5.434e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0068% · 101 / 1,490,806
0 hom · FAF 0.0069%

European (non-Finnish) 93 / 1,124,688	0.0083%
East Asian 3 / 39,896	0.0075%
African/African American 3 / 70,684	0.0042%
Remaining individuals 1 / 57,670	0.0017%
South Asian 1 / 76,142	0.0013%

+ 5 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0064% · 8 / 125,122
0 hom · FAF 0.0054%

African/African American 2 / 13,726	0.015%
European (non-Finnish) 6 / 51,282	0.012%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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