About KLLN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KLLN c.373C>T, p.(Arg125Trp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
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
69 / 1,545,416 alleles
gnomAD v4.1: 69 / 1,545,416 alleles. Recorded AF 4.46482e-05. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=4.46e-05 (69/1
- 545
- 416
- 0 homozygotes)
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.138 (low
- not pathogenic)
- BayesDel: -0.0848766 (benign range)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
Not met · 22 · evaluated, threshold not reached
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. Details ▾Hide ▴
Evidence considered
- No established pathogenic variant at Arg125 in ClinVar.
Still missing
- No pathogenic comparators at Arg125.
Sources
PS2 No de novo data with confirmed maternity and paternity are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No family or de novo data available.
PS3 No well-established in vitro or in vivo functional studies have been identified for this specific variant. The available KLLN literature addresses promoter methylation and gene-level function but does not report functional data for NM_001126049.2:c.373C>T. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies found in the literature.
Still missing
- No functional assays performed for p.(Arg125Trp).
PS4 No case-control or cohort data demonstrate a statistically significant enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
- No prevalence data in affected populations.
Still missing
- No case-control studies available.
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. Details ▾Hide ▴
Evidence considered
- Not located in a significant hotspot
- no established critical domain for KLLN missense variants.
Still missing
- No established critical functional domain for KLLN missense variation.
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. No comparator candidates were found for PM5 assessment. Details ▾Hide ▴
Evidence considered
- No pathogenic missense comparators at Arg125 identified.
Still missing
- No same-residue pathogenic comparators available.
Sources
clinvar ↗pm5_candidates
PM6 No de novo observation (with or without confirmed parentage) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo data available.
PP1 No cosegregation data in affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data identified.
Still missing
- No family studies available.
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. Details ▾Hide ▴
Evidence considered
- HCI prior not available for KLLN
- no missense constraint data.
Still missing
- No missense constraint metrics available for KLLN.
PP3 Multiple in silico predictors do not support a damaging effect. REVEL score is 0.138 (below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta = 0.00). These results are not consistent with a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.138 (low
- not pathogenic)
- BayesDel: -0.0848766 (benign direction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP4 No patient phenotype or family history data are available for this variant. No information about the clinical presentation of individuals carrying this variant has been provided. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available.
Still missing
- No clinical phenotype information provided for the proband.
PP5 No reputable source (clinical laboratory, expert panel, or research group) has reported this variant as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic assertions from reputable sources.
Still missing
- No pathogenic assertions from any source.
Sources
BA1 The allele frequency in gnomAD v4.1 is 0.00446% (69/1,545,416), which is well below the 1% threshold for BA1. Details ▾Hide ▴
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. Details ▾Hide ▴
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. Cowden syndrome/PTEN hamartoma tumor syndrome exhibits age-related penetrance, and no specific adult control genotype-phenotype data are available for this variant to satisfy BS2. Details ▾Hide ▴
Evidence considered
- 69 alleles in gnomAD v4.1
- but no phenotype-confirmed healthy adult observations and Cowden syndrome has age-related penetrance.
Still missing
- No phenotype data for gnomAD carriers
- cannot confirm healthy status.
Sources
BS3 No well-established functional studies demonstrating no damaging effect have been identified for NM_001126049.2:c.373C>T. Details ▾Hide ▴
Evidence considered
- No benign functional data available for this variant.
Still missing
- No variant-specific functional studies.
BS4 No nonsegregation data in affected families are available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data to assess nonsegregation.
Still missing
- No family studies available.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. While KLLN loss of function is implicated in Cowden syndrome, the established germline disease mechanism is promoter hypermethylation (epigenetic silencing) rather than coding truncating variants. The variant spectrum of KLLN in germline disease is not sufficiently defined to apply BP1. Details ▾Hide ▴
Evidence considered
- KLLN germline disease mechanism is primarily promoter hypermethylation
- not established that coding truncating variants are the predominant pathogenic mechanism.
Still missing
- Insufficiently characterized germline variant spectrum for KLLN.
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. Details ▾Hide ▴
Evidence considered
- No in trans observations reported.
Still missing
- No phase data with pathogenic variants.
BP5 No observation of this variant in a case with an alternative established molecular basis for disease has been reported. Details ▾Hide ▴
Evidence considered
- No cases with an alternate molecular diagnosis identified.
Still missing
- No coexisting molecular diagnoses reported.
BP6 No reputable source has reported this variant as benign in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no benign assertions from reputable sources.
Still missing
- No benign assertions from any source.
Sources
PS5 This variant is absent from ClinVar. No reputable sources have reported it as pathogenic. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic assertions.
Still missing
- No ClinVar submissions for this variant.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.373C>T, p.Arg125Trp). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
PM3 N/AKLLN-associated Cowden syndrome is an autosomal dominant disorder. PM3 applies only to recessive disorders where a variant is observed in trans with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- Autosomal dominant disorder
- PM3 is for recessive conditions only.
PM4 N/AThis is a single nucleotide substitution producing a missense change, not a protein-length-altering variant (in-frame indel, stop-loss, or initiation codon change). PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution
- PM4 applies to protein-length changes only.
BP3 N/AThis is a substitution variant, not an in-frame indel. BP3 applies only to in-frame deletions or insertions in non-repeat regions. Details ▾Hide ▴
Evidence considered
- Substitution
- not an in-frame indel.
BP7 N/AThis is a missense variant (c.373C>T, p.Arg125Trp), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Identifiers
- Gene
- KLLN
- Transcript
- NM_001126049.2
- Coding (HGVS c.)
- NM_001126049.2:c.373C>T
- Protein (HGVS p.)
- NP_001119521.1:p.(Arg125Trp)
- GRCh38
- chr10:87862115 G>A
- GRCh37
- chr10:89621872 G>A
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KLLN
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
69 / 1,545,416 alleles
AF 4.46e-05 · 0 homozygotes · FAF 4.68e-05
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.5e-05 · 69 / 1,545,416 alleles · 0 hom · FAF 4.7e-05
| European (non-Finnish)67 / 1,143,334 | 5.9e-05 |
| Remaining individuals1 / 59,808 | 1.7e-05 |
| South Asian1 / 83,550 | 1.2e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.138
- BayesDel
- -0.085
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.138 (low
- not pathogenic)
- BayesDel: -0.0848766 (benign range)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP3 Multiple in silico predictors do not support a damaging effect. REVEL score is 0.138 (below typical pathogenic thresholds), BayesDel score is -0.085 (benign direction), and SpliceAI predicts no splice impact (max delta = 0.00). These results are not consistent with a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.138 (low
- not pathogenic)
- BayesDel: -0.0848766 (benign direction)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.373C>T, p.Arg125Trp), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.138. BayesDel score = -0.0848766.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
69 / 1,545,416 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
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001126049.2%3Ac.373C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89621872-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87862115-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87862115-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001126049.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/KLLN/R125W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KLLN+c.373C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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= 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.138. BayesDel score = -0.0848766.
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.