NM_001126049.2:c.184C>G

KLLN · NP_001119521.1:p.(Arg62Gly) · NM_001126049.2

GRCh37: chr10:89622061 G>C · GRCh38: chr10:87862304 G>C

Gene: KLLN Transcript: NM_001126049.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP1 supporting benign BP4 supporting benign

Variant details

Gene

KLLN

Transcript

NM_001126049.2

Protein

NP_001119521.1:p.(Arg62Gly)

gnomAD AF

0.00039053236134167844 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001126049.2:c.184C>G (p.Arg62Gly) in KLLN is classified as Benign based on ACMG/AMP 2015 criteria.

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.

BS1 (strong benign): gnomAD v4.1 grpmax FAF of 1.376% also exceeds the 0.3% BS1 threshold, providing additional independent benign evidence.

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.

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.

No pathogenic criteria were met. PVS1 is not applicable (missense variant). PS1-PS4, PM1-PM2, PM5-PM6, and PP1-PP5 all lacked supporting evidence.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	NM_001126049.2:c.184C>G (p.Arg62Gly) is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 applies only to null variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at the same amino acid position (Arg62) previously established as pathogenic. No ClinVar pathogenic comparators at this residue identified in PM5 candidate search.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence data available. No reports of confirmed maternity and paternity testing for this variant.
PS3	Not met	No variant-specific functional experimental data for NM_001126049.2:c.184C>G (p.Arg62Gly) or a systematically characterized range encompassing this residue. Published KLLN functional studies (PMID:26673699, PMID:30245854) investigate gene-level mechanisms (H3K9me3 maintenance, DNA damage response) via overexpression/knockdown but do not test this missense variant. These gene-level studies do not satisfy PS3's requirement for variant-specific or systematically ranged functional characterization.	pvs1_gene_context
PS4	Not met	No case-control or cohort enrichment data available. The variant has not been reported in affected individuals beyond a single ClinVar submission classifying it as VUS.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. The standard pathogenic criteria are PVS1, PS1-4, PM1-6, PP1-5. No applicable evidence type maps to this criterion slot.
PM1	Not met	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. While KLLN has a characterized DNA-binding function, the specific functional domains and critical residues have not been systematically mapped in the literature at the resolution needed for PM1.
PM2	Not met	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. The larger, more diverse v4.1 dataset supersedes v2.1, and PM2 cannot be applied when the variant is common in any population sub-group.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic comparator variants at the same amino acid residue (Arg62) identified in ClinVar. The automated PM5 candidate search found zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo reports available for this variant. PM6 requires observation of a de novo event (without confirmation of paternity and maternity).
PP1	Not met	No segregation data available. No family studies have been reported for this variant.
PP2	Not met	KLLN does not have an established low rate of benign missense variation. gnomAD v4.1 data shows this missense variant is common in East Asian populations (AF 1.47%, 5 homozygotes), suggesting benign missense variation in this gene may not be rare. No PP2 gene-specific constraint metrics available.	gnomad_v4
PP3	Not met	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). All in silico predictors are consistent with a benign interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data available for assessment. The single ClinVar submission does not include phenotype details, and no clinical case reports describe this variant in affected individuals.	clinvar
PP5	Not met	ClinVar classification is Uncertain Significance (single submitter: Revvity Omics), not Pathogenic. No reputable source has reported this variant as pathogenic.	clinvar
BA1	Met	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
BS1	Met	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
BS2	Not met	While gnomAD v4.1 reports 5 homozygotes in the East Asian population, BS2 requires confirmed observation in healthy adult individuals. gnomAD does not provide individual-level phenotype confirmation, and heterozygous observation alone in a population database does not satisfy BS2 for a dominant disorder. The homozygous count is suggestive but insufficient without confirmed healthy status.	gnomad_v4
BS3	Not met	No functional studies demonstrating no damaging effect for this specific variant. KLLN functional studies (PMID:26673699, PMID:30245854) are gene-level mechanistic studies that do not test p.Arg62Gly.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease. No family studies have been reported for this variant.
BP1	Met	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.	pvs1_gene_context
BP2	N/A	BP2 applies to missense variants in genes where primarily missense variants cause disease. KLLN's primary disease mechanism is promoter hypermethylation, not missense coding changes; this is the inverse scenario (see BP1).
BP4	Met	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 bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternative molecular basis for disease. No clinical reports describe this variant co-occurring with another established pathogenic variant.
BP6	Not met	ClinVar classification is Uncertain Significance, not Benign. The single submitter (Revvity Omics) does not assert benign, and no reputable source has reported this variant as benign without sharing supporting data.	clinvar
BP7	N/A	NM_001126049.2:c.184C>G is a missense variant (p.Arg62Gly), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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