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KLLNc.184C>GBenign
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Variant interpretation report

KLLN c.184C>G, p.(Arg62Gly)

NM_001126049.2:c.184C>G NP_001119521.1:p.(Arg62Gly) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About KLLN

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 4
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone

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.

BS1Strong
BS1 · strong

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.

BP1Supporting
BP1 · supporting

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.

BP4Supporting
BP4 · supporting

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.

Recorded classification: Benign

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
606 / 1,551,728 alleles

gnomAD v4.1: 606 / 1,551,728 alleles. Recorded AF 0.000390532. Recorded homozygote count 5.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · BA1, BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 18 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 4

BA1 Stand alonegnomAD 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: grpmax FAF 1.376%
  • EAS AF 1.47% (603/40
  • 920 alleles
  • 5 homozygotes).
Sources
gnomad_v4 ↗
BS1 StronggnomAD 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF 1.376% > 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BP1 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • KLLN disease mechanism in Cowden syndrome is primarily germline promoter hypermethylation (epigenetic silencing)
  • not missense coding variants.
Sources
pvs1_gene_context
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.102 (not deleterious)
  • BayesDel -0.317 (benign)
  • SpliceAI 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at Arg62 with a different nucleotide change identified in ClinVar or literature.
Still missing
  • No residue-level comparator data available.
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence data available. No reports of confirmed maternity and paternity testing for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar submissions or literature.
Still missing
  • No family-based testing 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. 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. Details ▾Hide ▴
Evidence considered
  • KLLN gene-level functional studies exist (ChIP-seq
  • apoptosis assays) but no variant-specific functional data for p.Arg62Gly.
Still missing
  • No experimental functional characterization of p.Arg62Gly.
Sources
pvs1_gene_context
PS4 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. Details ▾Hide ▴
Evidence considered
  • Single ClinVar submission (SCV003810078
  • Revvity Omics) with VUS classification
  • no case-control studies.
Still missing
  • No case-control or cohort studies comparing affected vs. unaffected individuals.
Sources
clinvar ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org reports no significant hotspot at this residue.
Still missing
  • No high-resolution functional domain map of KLLN available.
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. 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.0078% (12/154
  • 100)
  • gnomAD v4.1 AF 0.039% overall but EAS AF 1.47% with 5 homozygotes
  • PM2 contraindicated by v4.1 data.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM5 No pathogenic comparator variants at the same amino acid residue (Arg62) identified in ClinVar. The automated PM5 candidate search found zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no same-residue pathogenic comparators at Arg62.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo reports available for this variant. PM6 requires observation of a de novo event (without confirmation of paternity and maternity). Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No family-based testing data.
PP1 No segregation data available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation data available.
Still missing
  • No family studies reported.
PP2 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 shows high frequency of this missense variant in EAS
  • no evidence KLLN has low benign missense rate.
Still missing
  • No gene-level missense constraint metrics for KLLN.
Sources
gnomad_v4 ↗
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). All in silico predictors are consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.102 (not deleterious)
  • BayesDel -0.317 (benign)
  • SpliceAI 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No phenotype data reported for variant carriers.
Still missing
  • No clinical phenotype information available.
Sources
clinvar ↗
PP5 ClinVar classification is Uncertain Significance (single submitter: Revvity Omics), not Pathogenic. No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS
  • criteria provided
  • single submitter
  • no pathogenic assertion.
Sources
clinvar ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • 5 homozygotes in gnomAD v4.1 EAS
  • but phenotype status unconfirmed.
Still missing
  • No confirmed healthy adult carriers documented.
Sources
gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • No variant-specific benign functional data available.
Still missing
  • No experimental functional characterization of p.Arg62Gly.
BS4 No segregation data demonstrating lack of cosegregation with disease. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family-based cosegregation studies.
BP5 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. Details ▾Hide ▴
Evidence considered
  • No alternative molecular diagnosis reported in variant carriers.
Still missing
  • No clinical reports of co-occurring pathogenic variants.
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS only
  • no benign assertion from a reputable source.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
  • Variant classified as missense (p.Arg62Gly)
  • falls outside PVS1 null-variant buckets.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP2 N/ABP2 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). Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.
PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
KLLN
Transcript
NM_001126049.2
Coding (HGVS c.)
NM_001126049.2:c.184C>G
Protein (HGVS p.)
NP_001119521.1:p.(Arg62Gly)
GRCh38
chr10:87862304 G>C
GRCh37
chr10:89622061 G>C
ClinVar
2433170

Gene diagram

Every interpreted variant in KLLN, mapped onto the exon structure of NM_001126049.2. Select a row to find it on the plot.

KLLNNM_001126049.2
Fetching transcript structure from UCSC…
gnomAD v4.1 606 / 1,551,728 alleles AF 0.000391 · 5 homozygotes · FAF 0.0138
gnomAD v2.1 12 / 154,100 alleles AF 7.79e-05 · 0 homozygotes · FAF 0.000565
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00039 · 606 / 1,551,728 alleles · 5 hom · FAF 0.014
East Asian603 / 40,920 0.0155 hom
Remaining individuals3 / 60,116 5e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 7.8e-05 · 12 / 154,100 alleles · 0 hom · FAF 0.00057
East Asian11 / 10,900 0.001
Remaining individuals1 / 4,340 0.00023
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -471 bp
0.000
SpliceAI acceptor gainat -56 bp
0.000
SpliceAI donor lossat +354 bp
0.000
SpliceAI donor gainat +99 bp
0.000

Other predictors

REVEL
0.102
BayesDel
-0.317

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.102 (not deleterious)
  • BayesDel -0.317 (benign)
  • SpliceAI 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
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). All in silico predictors are consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.102 (not deleterious)
  • BayesDel -0.317 (benign)
  • SpliceAI 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.102. BayesDel score = -0.317459.

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Richards S et al. · 2015
    Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. This paper provides the generic ACMG/AMP classification framework used for variant adjudication but does not discuss NM_001126049.2:c.184C>G, KLLN, or p.Arg62Gly.
    Does not name this variant
    PMID 25741868 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 606 / 1,551,728 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.