NM_001126049.2:c.373C>T (p.Arg125Trp) is a missense variant in KLLN, a gene implicated in Cowden syndrome and Cowden-like syndrome through germline promoter hypermethylation. This variant is absent from ClinVar and has not been reported as pathogenic or benign by any clinical laboratory or expert panel.1 In gnomAD v4.1, the variant is observed at an extremely low allele frequency (0.00446%, 69/1,545,416 alleles, 0 homozygotes; grpmax FAF=4.68e-05), meeting PM2 at supporting strength. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.2 Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.138 (low, below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta 0.00). These concordant benign predictions meet BP4 at supporting strength.3 No variant-specific functional studies, case-control data, de novo observations, family segregation data, or clinical phenotype information are available. PVS1 is not applicable to this missense variant; PM1, PS3, PS4, PM5, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP5, and BP6 are not met due to insufficient evidence. Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting) are present. These offset, resulting in a final classification of Variant of Uncertain Significance (VUS).4
KLLN
Final classification
VUS
KLLN c.373C>T · p.Arg125Trp
KLLN
NM_001126049.2:c.373C>T (p.Arg125Trp) is a missense variant in KLLN, a gene implicated in Cowden syndrome and Cowden-like syndrome through germline promoter hypermethylation.
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
KLLN c.373C>T
PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001126049.2 · variants mapped to exon structure
KLLN
NM_001126049.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present in gnomAD v4.1 at an extremely low allele frequency (AF=0.00446%, 69/1,545,416 alleles, 0 homozygotes; grpmax FAF=4.68e-05), well below the 0.1% threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
gnomAD v4.1: AF=4.46e-05 (69/1545416
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious impact. The REVEL score is 0.138 (below the 0.5 threshold commonly associated with pathogenicity), the BayesDel score is -0.085 (in the benign range; negative values favor benign), and SpliceAI predicts no splice alteration (max delta = 0.00). These concordant predictions from independent in silico tools support a benign interpretation.
REVEL: 0.138 (lownot pathogenic)BayesDel: -0.0848766 (benign range)
Assessed · not applied
Pathogenic
PS1
No pathogenic or likely pathogenic variant at the same amino acid position (Arg125) has been established in ClinVar or the literature to support that this same amino acid change is known to be pathogenic.
PS2
No de novo data with confirmed maternity and paternity are available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for this specific variant.
PS4
No case-control or cohort data demonstrate a statistically significant enrichment of this variant in affected individuals versus controls.
PM1
This variant does not lie within a statistically significant mutational hotspot in COSMIC or Cancer Hotspots, and no well-established critical functional domain has been defined for KLLN where missense variants are enriched in disease.
PM5
No pathogenic or likely pathogenic missense variants at the same amino acid residue (Arg125) with a different alternate amino acid have been identified in ClinVar or the literature.
PM6
No de novo observation (with or without confirmed parentage) has been reported for this variant.
PP1
No cosegregation data in affected family members are available for this variant.
PP2
No gene-level missense constraint metrics (e.g., missense Z-score, HCI prior probability) are available for KLLN to assess whether the gene has a low rate of benign missense variation.
PP3
Multiple in silico predictors do not support a damaging effect.
PP4
No patient phenotype or family history data are available for this variant.
PP5
No reputable source (clinical laboratory, expert panel, or research group) has reported this variant as pathogenic in ClinVar or the literature.
Benign
BA1
The allele frequency in gnomAD v4.1 is 0.00446% (69/1,545,416), which is well below the 1% threshold for BA1.
BS1
The allele frequency in gnomAD v4.1 is 0.00446% (69/1,545,416), which is well below the 0.3% threshold for BS1.
BS2
Although 69 alleles are observed in gnomAD v4.1 (a general population database), BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for NM_001126049.2:c.373C>T.
BS4
No nonsegregation data in affected families are available for this variant.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant in KLLN or PTEN has been reported for a fully penetrant dominant disorder.
BP5
No observation of this variant in a case with an alternative established molecular basis for disease has been reported.
BP6
No reputable source has reported this variant as benign in ClinVar or the literature.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.46482e-05; MAF= 0.00446%, 69/1545416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.86005e-05; MAF= 0.00586%, 67/1143334 alleles, homozygotes = 0); grpmax FAF= 4.681e-05.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0045%
· 69 / 1,545,416
0 hom · FAF 0.0047%
0 hom · FAF 0.0047%
European (non-Finnish) 67 / 1,143,334 |
0.0059% |
Remaining individuals 1 / 59,808 |
0.0017% |
South Asian 1 / 83,550 |
0.0012% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.138. BayesDel score = -0.0848766.
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