NM_000455.5:c.249G>A (p.Lys83=) is a synonymous variant in STK11 with no predicted effect on splicing (SpliceAI max delta=0.00).1 The variant is present at extremely low frequency in gnomAD (v2.1: 2/272,834 alleles, AF=0.00073%; v4.1: 6/1,611,652 alleles, AF=0.00037%), satisfying PM2 at supporting level.2 ClinVar consensus from 5 clinical laboratories classifies this variant as Likely benign/Benign (ClinVar ID 486990), supporting BP6 at supporting strength.3 As a synonymous variant with no predicted splice impact, BP7 applies at supporting strength.4 Computational evidence shows no deleterious effect, satisfying BP4 at supporting strength.5 No functional studies, case-control data, segregation data, or de novo reports were identified for this variant. PP5 is not met as ClinVar reports a benign classification. PS3, PS4, and PP3 are not met.6 PVS1, PS1, PM1, PM5, PP2, and BP1 are not applicable as the variant is synonymous with no amino acid change. BA1, BS1 thresholds are not met due to extremely low population frequency.7 Overall, the evidence profile shows 1 supporting pathogenic criterion (PM2) versus 3 supporting benign criteria (BP4, BP6, BP7). The net classification is Likely benign by ACMG/AMP 2015 combination rules.8
STK11
Final classification
Likely Benign
STK11 c.249G>A · p.Lys83=
STK11
NM_000455.5:c.249G>A (p.Lys83=) is a synonymous variant in STK11 with no predicted effect on splicing (SpliceAI max delta=0.00).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP6 supporting, BP7 supporting; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6BP7
Likely Benign
STK11 c.249G>A
PM2 + BP4 + BP6 + BP7
→
Likely Benign
7
gnomad_v2 ↗gnomad_v4 ↗pvs1_variant_assessment
8
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 · 15 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000455.5:c.249G>A is present at extremely low frequency in gnomAD v2.1 (AF=0.00073%, 2/272,834 alleles, 0 homozygotes) and gnomAD v4.1 (AF=0.00037%, 6/1,611,652 alleles, grpmax FAF=7.9e-7). This is well below the 0.1% threshold for PM2.
gnomAD v2.1 total AF=7.33e-6 (2/272834)gnomAD v4.1 total AF=3.72e-6 (6/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest NM_000455.5:c.249G>A has no deleterious impact. SpliceAI predicts no splice alteration (max delta=0.00). REVEL and BayesDel are not applicable to synonymous variants, which is itself consistent with a lack of predicted functional effect.
SpliceAI max delta=0.00no in silico predictor suggests pathogenicity.
✓
BP6
supporting
Benign
ClinVar classifies NM_000455.5:c.249G>A as Likely benign/Benign with consensus across 5 clinical laboratories (Ambry Genetics, Color Health, Invitae/Labcorp, All of Us, Myriad Genetics). Although review status is criteria provided single submitter per submission, the aggregate agreement of 5 independent clinical laboratories provides reputable source evidence for a benign classification.
ClinVar ID 486990: 5 clinical laboratory submissions all classify as Benign or Likely benign (3 Likely benign1 Likely Benign1 Benign).
✓
BP7
supporting
Benign
NM_000455.5:c.249G>A is a synonymous variant (p.Lys83=) for which SpliceAI predicts no impact on splicing (max delta score=0.00). There is no evidence of an effect on the splice consensus sequence or creation of a cryptic splice site. The variant meets BP7 criteria for a synonymous variant with no predicted splice alteration.
SpliceAI max delta=0.00synonymous variant with no predicted splice impact.
Assessed · not applied
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No functional studies were identified for NM_000455.5:c.249G>A (p.Lys83=).
PS4
No case-control or cohort data are available to assess variant prevalence in affected individuals versus controls.
PM6
No confirmed de novo occurrence of NM_000455.5:c.249G>A has been reported in the literature or ClinVar submissions.
PP1
No segregation data are available for NM_000455.5:c.249G>A.
PP3
No in silico predictors support pathogenicity for NM_000455.5:c.249G>A.
PP4
No patient phenotype or clinical data are available in this case to assess whether the proband's phenotype is specific for STK11-associated disease (Peutz-Jeghers syndrome).
PP5
ClinVar classifies NM_000455.5:c.249G>A as Likely benign (ClinVar ID 486990, review status: criteria provided, single submitter).
Benign
BA1
The maximum allele frequency of NM_000455.5:c.249G>A in gnomAD v2.1 is 0.0016% (European non-Finnish) and in gnomAD v4.1 is 0.0016% (Remaining individuals).
BS1
The maximum allele frequency of NM_000455.5:c.249G>A is 0.0016% in gnomAD, which is below the 0.3% BS1 threshold for a dominant disorder such as Peutz-Jeghers syndrome.
BS2
No data are available regarding observation of NM_000455.5:c.249G>A in healthy adults with full penetrance expected.
BS3
No functional studies demonstrating a benign effect have been identified for NM_000455.5:c.249G>A.
BS4
No segregation data are available for NM_000455.5:c.249G>A.
BP2
No data are available regarding observation of NM_000455.5:c.249G>A in trans with a pathogenic STK11 variant.
BP5
No data are available regarding an alternative molecular cause of disease in the proband.
N/A · 9
PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.72289e-06; MAF= 0.00037%, 6/1611652 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60256e-05; MAF= 0.00160%, 1/62400 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.33046e-06; MAF= 0.00073%, 2/272834 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.60601e-05; MAF= 0.00161%, 2/124532 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,611,652
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
Remaining individuals 1 / 62,400 |
0.0016% |
South Asian 1 / 90,692 |
0.0011% |
European (non-Finnish) 4 / 1,178,956 |
0.00034% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00073%
· 2 / 272,834
0 hom
0 hom
European (non-Finnish) 2 / 124,532 |
0.0016% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 486990)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25645574 ↗
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
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
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
27854360 ↗
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR