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NM_001126049.2:c.-535_-534insC
p.? · KLLN
ACMG/AMP
0%
complete
Final classification
VUS
PM2BP4
KLLN
c.-535_-534insC
p.?
unknown · exon 1
Gene context NCBI Gene ↗

KLLN encodes a small nuclear protein that binds DNA and inhibits DNA synthesis, halting cells in the S phase of the cell cycle and steering them toward programmed cell death (apoptosis). Its production is switched on by p53, a central tumor-suppressor protein, placing KLLN within a key growth-control pathway. Through this growth-suppressing and apoptosis-promoting activity, KLLN is considered part of the cell's natural defense against cancer, though no specific inherited disease syndrome is firmly tied to the gene.

This variant

KLLN's p53-driven growth-suppressor role ties it to cancer defense rather than to a specific inherited syndrome, so this variant is judged on molecular evidence alone. Classified as a variant of uncertain significance (VUS), this 5' untranslated region insertion leaves the KLLN protein unchanged, is absent from population reference datasets, and shows no predicted splice impact. Whether it alters KLLN's cancer-protective activity from the promoter region remains unknown without functional or familial data.

Transcript
NM_001126049.2
HGVS · transcript:coding
NM_001126049.2:c.-535_-534insC
GRCh38
chr10:87863021 A>AG
GRCh37
chr10:89622778 A>AG
Because no KLLN-specific ClinGen or local classification framework exists, generic ACMG/AMP 2015 rules were applied. The only applied evidence, PM2 (supporting) for pathogenicity and BP4 (supporting) for benignity, meets no Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold, so the variant is a variant of uncertain significance (VUS).
Classification rationale
PM2 BP4 VUS
KLLN c.-535_-534insC unknown · exon 1

PM2 (Supporting): the 5' untranslated region insertion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population reference datasets. BP4 (Supporting): SpliceAI maximum delta score 0.022 is below the 0.1 threshold, predicting no significant splice impact. Overall classification: VUS - the conflicting PM2 (supporting) and BP4 (supporting) evidence meets no ACMG/AMP 2015 Pathogenic or Benign combination threshold.

PM2 + BP4 → VUS
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.
Gene diagram · NM_001126049.2 · variants mapped to exon structure
KLLN NM_001126049.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met (supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population reference datasets.
The consolidated evidence reports absence of the variant from gnomAD v2.1.The consolidated evidence reports absence of the variant from gnomAD v4.1.The consolidated evidence reports absence of the variant from gnomAD-Canada v1.0.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 supporting Benign
Met (supporting): SpliceAI maximum delta 0.022 falls below the 0.1 BP4 threshold, predicting no significant splice impact.
No KLLN VCEP/CSPEC or local gene-specific computational-evidence framework was retrieved; the generic ACMG fallback governs.SpliceAI for NM_001126049.2:c.-535_-534insC reports DS_AG 0.014, DS_AL 0.003, DS_DG 0.007, and DS_DL 0.022 (maximum delta 0.022). The generic non-missense calibration assigns BP4 supporting when maximum delta is <0.1.
spliceai ↗
Assessed · not applied · 5 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no de novo occurrence with confirmed maternity/paternity and absence of the variant in both parents is documented.
PS3 Not assessed: no validated functional assay result for this specific insertion was available.
PS4 Not assessed: no case series, case-control comparison, or enrichment statistic for this exact insertion was available.
PM3 Not assessed: no affected-proband observations, phase data, or co-occurring pathogenic alleles were identified.
PM6 Not assessed: no suspected de novo occurrence without confirmed parental testing is documented.
PP1 Not assessed: no affected relatives, familial genotypes, or phenotype-segregation data were identified.
PP3 Not met: SpliceAI maximum delta 0.022 does not exceed the >0.2 PP3 threshold.
PP4 Not assessed: no phenotype or clinical information for the carrier was provided, so phenotype specificity cannot be evaluated.
PP5 Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to support it.
Benign
BA1 Not met: the variant is absent from population databases, so no allele frequency exceeds the stand-alone benign threshold.
BS1 Not met: the variant is absent from population datasets, so no allele frequency exceeds the benign threshold for the relevant disorder.
BS2 Not assessed: no unaffected adult carriers or unaffected homozygotes with phenotype information were identified.
BS3 Not assessed: no validated functional study demonstrating a normal effect of this variant was available.
BS4 Not assessed: no variant-carrying family members or informative non-segregation observations were documented.
BP2 Not assessed: no phase observations or co-occurring pathogenic variants were identified to establish a trans/cis relationship.
BP5 Not assessed: no alternative causal diagnosis was documented to determine whether another finding explains the phenotype.
BP6 Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists to support it.
N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC