Variant classification summary

NM_000455.5:c.734+17C>G

STK11 · NP_000446.1:p.? · NM_000455.5

GRCh37: chr19:1220733 C>G · GRCh38: chr19:1220734 C>G

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP4 supporting BP6 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.?

gnomAD AF

1.8743533480949073e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000455.5:c.734+17C>G is an intronic variant in STK11 at position +17 of intron 5. No CSPEC/VCEP framework exists for STK11; classification follows generic ACMG/AMP 2015 rules (PMID:25741868).

2

This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00227% (6/264,478 alleles) and gnomAD v4.1 allele frequency 0.00187% (30/1,600,552 alleles), with no homozygotes observed (PM2_Supporting).

3

SpliceAI predicts no significant splicing impact (max delta score = 0.01), and multiple lines of computational evidence suggest no effect on gene product or splicing (BP4_Supporting).

4

This variant has been independently classified as Likely benign by 4 clinical laboratories and Benign by 2 clinical laboratories in ClinVar (Variation ID 379077), all with criteria provided (BP6_Supporting).

5

No functional studies, de novo observations, segregation data, or case-control data were identified for this specific variant in the available literature. The 15 PubMed-indexed references associated with this ClinVar entry are practice guidelines and review articles that do not mention NM_000455.5:c.734+17C>G.

6

Applying generic ACMG/AMP 2015 final combination rules: 1 supporting pathogenic criterion (PM2_Supporting) and 2 supporting benign criteria (BP4_Supporting, BP6_Supporting). With ≥2 supporting benign criteria, this variant is classified as Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This intronic variant at position +17 of intron 5 does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework is not applicable.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No prior pathogenic variant at the same amino acid change exists; this is an intronic variant with no amino acid consequence.
PS2	Not assessed	No de novo evidence identified for this variant. The exploratory literature search did not return usable results, and none of the 15 PubMed-indexed references associated with this ClinVar entry mention NM_000455.5:c.734+17C>G.
PS3	Not assessed	No functional studies were identified for this specific variant. The ClinVar-associated PMIDs are practice guidelines and review articles, not experimental functional assays.
PS4	Not assessed	No case-control or case series data were identified for this variant. ClinVar-associated PMIDs are practice guidelines and general review articles that do not report variant-specific prevalence data.
PS5	N/A	No reputable source has recently reported this variant as pathogenic. ClinVar classification is Likely benign/Benign from 6 clinical laboratories.	clinvar
PM1	N/A	This is an intronic variant at position +17 of intron 5, not located in a known mutational hotspot or well-characterized critical functional domain.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00227% (6/264,478 alleles), gnomAD v4.1 allele frequency 0.00187% (30/1,600,552 alleles), both well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; this is an intronic variant with no amino acid change. No comparator candidates available.	pm5_candidates
PM6	Not assessed	No de novo evidence identified. Same assessment as PS2 for this intronic variant.
PP1	Not assessed	No segregation data were identified for this variant in the available literature.
PP2	N/A	This is an intronic variant, not a missense variant. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	SpliceAI predicts no significant splicing impact (max delta score = 0.01). REVEL and BayesDel scores are not available for this intronic variant. Multiple lines of in silico evidence do not support a deleterious effect.	spliceai
PP4	Not assessed	No phenotype specificity data are available for this variant. The ClinVar-associated publications are general practice guidelines that do not provide variant-level phenotype data.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar reports this variant as Likely benign (4 clinical laboratories) and Benign (2 clinical laboratories).	clinvar
BA1	Not met	The allele frequency in gnomAD v2.1 (0.00227%) and v4.1 (0.00187%) is far below the 1% BA1 threshold for standing as a benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD v2.1 (0.00227%) and v4.1 (0.00187%) is far below the 0.3% BS1 threshold. The highest subpopulation frequency (African/African American, 0.02273% in v4.1) also falls below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No specific evidence of this variant observed in healthy adults beyond its presence at low frequency in gnomAD population databases. The variant has been observed in 36 total alleles across gnomAD v2.1 and v4.1 combined, but individual-level phenotype data are not available.
BS3	Not assessed	No well-established functional studies were identified demonstrating no damaging effect for this specific variant. SpliceAI prediction alone (max delta 0.01) is in silico evidence, not a functional assay qualifying for BS3.
BS4	Not assessed	No segregation data are available to assess lack of segregation with disease.
BP1	N/A	This is an intronic variant, not a missense variant. BP1 applies only to missense variants in genes where truncating variants are the primary disease mechanism.
BP2	Not assessed	No evidence of this variant observed in trans with a known pathogenic STK11 variant was identified in the available literature or databases.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a repetitive region.
BP4	Met	SpliceAI predicts no significant splicing impact for this intronic variant (max delta score = 0.01, well below the 0.1 threshold). Multiple lines of computational evidence suggest no impact on gene product or splicing.	spliceai
BP5	Not assessed	No evidence was identified of this variant observed in a case with an alternate molecular basis for disease.
BP6	Met	This variant has been classified as Likely benign by 4 clinical laboratories (Color Health, Genome-Nilou Lab, Rigshospitalet, Labcorp/Invitae) and Benign by 2 clinical laboratories (GeneDx, KCCC/NGS Laboratory) in ClinVar (Variation ID 379077), all with criteria provided.	clinvar
BP7	N/A	This is an intronic variant, not a synonymous (silent) variant. BP7 specifically applies to synonymous variants with no predicted splice impact. SpliceAI evidence is captured under BP4.
PM3	N/A	STK11-related Peutz-Jeghers syndrome is an autosomal dominant condition; PM3 (in trans with pathogenic variant) is not applicable.
PM4	N/A	This is a single-nucleotide substitution, not a protein-length-altering variant (in-frame deletion/insertion, stop-loss, or initiation codon change).

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.