Classification rationale

PM2 BP4 VUS

STK11 c.22C>G

The STK11 c.22C>G (p.Gln8Glu) variant has been reported in ClinVar as uncertain significance by five clinical laboratory submissions.¹ This variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, supporting rarity but not a benign frequency threshold.² Computational evidence supports no significant impact on splicing or protein function, with SpliceAI max delta score 0.00, REVEL 0.032, and BayesDel -0.435498.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

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

STK11 NM_000455.5

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.50785e-06; MAF= 0.00025%, 4/1594994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.41504e-06; MAF= 0.00034%, 4/1171290 alleles, homozygotes = 0); grpmax FAF= 8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.6322e-06; MAF= 0.00046%, 1/215880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.03814e-05; MAF= 0.00104%, 1/96326 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00025% · 4 / 1,594,994
0 hom · FAF 8e-05%

European (non-Finnish)

4 / 1,171,290

0.00034%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00046% · 1 / 215,880
0 hom

European (non-Finnish)

1 / 96,326

0.001%

+ 7 not observed (African/African American, 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 Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.032. BayesDel score = -0.435498.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots