NM_001126049.2:c.184C>G (p.Arg62Gly) in KLLN is classified as Benign based on ACMG/AMP 2015 criteria.1 BA1 (stand-alone benign): gnomAD v4.1 grpmax filtering allele frequency is 1.376%, exceeding the 1% threshold for a stand-alone benign classification. The East Asian subpopulation allele frequency is 1.47% (603 of 40,920 alleles) with 5 homozygotes, confirming this is a common population polymorphism inconsistent with a rare Mendelian disorder.2 BS1 (strong benign): gnomAD v4.1 grpmax FAF of 1.376% also exceeds the 0.3% BS1 threshold, providing additional independent benign evidence.3 BP1 (supporting benign): This is a missense variant in KLLN, where the established germline pathogenic mechanism in Cowden syndrome is promoter hypermethylation causing epigenetic silencing, not missense coding changes. The published literature demonstrates that KLLN pathogenicity is mediated by methylation status, not by coding sequence variants.4 BP4 (supporting benign): Multiple computational predictors consistently indicate no functional impact: REVEL score 0.102, BayesDel score -0.317 (benign), and SpliceAI max delta 0.00.5 No pathogenic criteria were met. PVS1 is not applicable (missense variant). PS1-PS4, PM1-PM2, PM5-PM6, and PP1-PP5 all lacked supporting evidence.
KLLN
Final classification
Benign
KLLN c.184C>G · p.Arg62Gly
KLLN
NM_001126049.2:c.184C>G (p.Arg62Gly) in KLLN is classified as Benign based on ACMG/AMP 2015 criteria.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP1 supporting benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP1BP4
Benign
KLLN c.184C>G
BA1 + BS1 + BP1 + BP4
→
Benign
Gene diagram
· NM_001126049.2 · variants mapped to exon structure
KLLN
NM_001126049.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 18 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
gnomAD v4.1 grpmax filtering allele frequency (FAF) is 1.376%, exceeding the 1% BA1 threshold. The East Asian subpopulation allele frequency is 1.47% (603/40,920 alleles) with 5 homozygotes, confirming this is a common population polymorphism.
gnomAD v4.1: grpmax FAF 1.376%EAS AF 1.47% (603/40920 alleles
✓
BS1
strong
Benign
gnomAD v4.1 grpmax FAF 1.376% exceeds the 0.3% BS1 threshold. This variant is too common in population databases to be a pathogenic cause of Cowden syndrome, a rare autosomal dominant disorder.
gnomAD v4.1 grpmax FAF 1.376% > 0.3% BS1 threshold.
✓
BP1
supporting
Benign
NM_001126049.2:c.184C>G is a missense variant in KLLN, a gene where the primary germline pathogenic mechanism in Cowden syndrome is promoter hypermethylation causing epigenetic silencing, not coding sequence missense changes. The established literature (PMID:21177507, PMID:25669429) demonstrates that germline KLLN pathogenicity is mediated by methylation, not by missense variants in the coding region.
KLLN disease mechanism in Cowden syndrome is primarily germline promoter hypermethylation (epigenetic silencing)not missense coding variants.
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently predict no impact: REVEL score 0.102 (below pathogenic threshold), BayesDel score -0.317 (benign prediction), and SpliceAI max delta 0.00 (no predicted splicing alteration). All three independent in silico predictors concur on a benign interpretation.
REVEL 0.102 (not deleterious)BayesDel -0.317 (benign)SpliceAI 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at the same amino acid position (Arg62) previously established as pathogenic.
PS2
No de novo occurrence data available.
PS3
No variant-specific functional experimental data for NM_001126049.2:c.184C>G (p.Arg62Gly) or a systematically characterized range encompassing this residue.
PS4
No case-control or cohort enrichment data available.
PM1
Residue 62 is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no published functional domain mapping specifically identifies Arg62 as a critical functional residue.
PM2
While the overall gnomAD v2.1 allele frequency (0.0078%) is below the 0.1% PM2 threshold, gnomAD v4.1 data shows this variant is a population polymorphism: grpmax FAF 1.376%, East Asian AF 1.47% (603/40,920 alleles) with 5 homozygotes.
PM5
No pathogenic comparator variants at the same amino acid residue (Arg62) identified in ClinVar.
PM6
No de novo reports available for this variant.
PP1
No segregation data available.
PP2
KLLN does not have an established low rate of benign missense variation.
PP3
Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.102 (well below the ~0.5 pathogenic threshold), BayesDel score -0.317 (predicts benign), SpliceAI max delta 0.00 (no predicted splice impact).
PP4
No patient phenotype data available for assessment.
PP5
ClinVar classification is Uncertain Significance (single submitter: Revvity Omics), not Pathogenic.
Benign
BS2
While gnomAD v4.1 reports 5 homozygotes in the East Asian population, BS2 requires confirmed observation in healthy adult individuals.
BS3
No functional studies demonstrating no damaging effect for this specific variant.
BS4
No segregation data demonstrating lack of cosegregation with disease.
BP5
No evidence that this variant has been observed in a case with an alternative molecular basis for disease.
BP6
ClinVar classification is Uncertain Significance, not Benign.
N/A · 3
PVS1 · BP2 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000390532; MAF= 0.03905%, 606/1551728 alleles, homozygotes = 5) and has highest observed frequency in the East Asian population (AF= 0.0147361; MAF= 1.47361%, 603/40920 alleles, homozygotes = 5); grpmax FAF= 0.013763.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.78715e-05; MAF= 0.00779%, 12/154100 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00100917; MAF= 0.10092%, 11/10900 alleles, homozygotes = 0); grpmax FAF= 0.00056514.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.039%
· 606 / 1,551,728
5 hom · FAF 1.4%
5 hom · FAF 1.4%
East Asian 603 / 40,920 |
1.5% 5 hom |
Remaining individuals 3 / 60,116 |
0.005% |
+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0078%
· 12 / 154,100
0 hom · FAF 0.057%
0 hom · FAF 0.057%
East Asian 11 / 10,900 |
0.1% |
Remaining individuals 1 / 4,340 |
0.023% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), 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 Uncertain significance (1 clinical laboratory). (ClinVarID = 2433170)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.102. BayesDel score = -0.317459.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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 · 1 PMID not cited in assessment
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