Variant classification summary

NM_000455.4:c.369G>A

STK11 · NP_000446.1:p.(Gln123=) · NM_000455.4

GRCh37: chr19:1218494 G>A · GRCh38: chr19:1218495 G>A

Gene: STK11 Transcript: NM_000455.4

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.4

Protein

NP_000446.1:p.(Gln123=)

gnomAD AF

0.0011403893685961559 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone Benign): allele frequency 2.117% in gnomAD African/African American, exceeding the >1% population threshold.

2

BS1 (Strong Benign): ancestry-specific allele frequency 2.117% (gnomAD v4.1), exceeding the >0.3% threshold.

3

BP4 (Supporting): SpliceAI max delta 0.003, below the <0.1 threshold, indicating no splice impact.

4

Under generic ACMG/AMP 2015 combination rules, BA1 alone is sufficient for Benign.

Final determination: Generic ACMG/AMP 2015 rule: a single stand-alone BA1 criterion is sufficient to classify a variant as Benign.

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	Not applicable: c.369G>A is a synonymous change (p.(Gln123=)), so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: as a synonymous change producing no altered amino acid, there is no residue change to compare against a known pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental testing data (e.g., de novo observation) was available for this variant.
PS3	Not assessed	Not assessed: no functional assay data (kinase activity, splicing, or other validated studies) was available for this variant.
PS4	Not assessed	Not assessed: no case-control study or affected-case series for this exact variant was available.
PM1	N/A	Not applicable: PM1 applies to missense variants only, and this is a synonymous change with no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Not met	Not met: the variant is present in gnomAD at ~0.114% (v4.1) overall with 25 homozygotes, above the <0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations, second pathogenic allele, or phase information was available.
PM4	N/A	Not applicable: no protein length change occurs, so there is nothing for this in-frame insertion/deletion or stop-loss criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue, so there is nothing to compare against a different pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no report of this variant arising de novo, with parental testing absent.
PP1	Not assessed	Not assessed: no affected or unaffected relatives with informative genotype data were reported, so cosegregation could not be evaluated.
PP2	N/A	Not applicable: PP2 evaluates missense constraint, and this synonymous variant contains no missense change.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta is 0.003, far below the >0.2 threshold required for PP3.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or clinical findings establishing a Peutz-Jeghers syndrome-specific presentation were provided.
PP5	Not met	Not met: the ClinVar record has no expert-panel submission (0), and laboratory assertions alone cannot support PP5.	clinvar
BA1	Met	Met (stand-alone benign): gnomAD African/African American allele frequency is 2.117% (23 homozygotes), exceeding the >1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Met	Met (strong benign): ancestry-specific frequency reaches 2.117% (African/African American, gnomAD v4.1), well above the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: homozygotes exist (25 in gnomAD v4.1), but their clinically unaffected status could not be confirmed.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay demonstrating normal or wild-type activity was available for this variant.
BS4	Not assessed	Not assessed: no affected relatives lacking the variant were documented, so absence of segregation could not be shown.
BP1	N/A	Not applicable: BP1 addresses missense variants in truncating-disease genes, and this is a synonymous change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of this variant in trans or in cis with a pathogenic variant was documented.
BP3	N/A	Not applicable: no in-frame insertion/deletion or protein length change exists, so there is nothing for BP3 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta is 0.003, well below the <0.1 threshold for BP4.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the patient's phenotype was documented.
BP6	Not met	Not met: no ClinVar expert-panel benign assertion exists for this variant (0 expert-panel submissions).	clinvar
BP7	Not assessed	Not assessed: splice impact is minimal, but no nucleotide-conservation metric was available to complete the required pair of conditions.	spliceai

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.