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KLLNc.-535_-534insCUncertain significance
Print report
Variant interpretation report

KLLN c.-535_-534insC, p.?

NM_001126049.2:c.-535_-534insC NP_001119521.1:p.? Unknown · exon 1 View identifiers
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.

About KLLN

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.

NCBI Gene ↗
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

Met (supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population reference datasets.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met (supporting): SpliceAI maximum delta 0.022 falls below the 0.1 BP4 threshold, predicting no significant splice impact.

Recorded classification: Uncertain significance

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).

02The sources

Evidence at a glance

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

SpliceAI score
0.022 maximum delta

Recorded SpliceAI maximum delta score: 0.022. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
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 ↗
Somatic evidence
No matching record reported

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

Context only COSMIC ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 5 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

No KLLN VCEP/CSPEC or local gene-specific framework was available; generic ACMG/AMP consequence criteria were used.

The variant is a 5′ UTR insertion upstream of the CDS with no predicted protein change, so none of PVS1, PM4, or BP3 applies.

No KLLN VCEP/CSPEC or local gene-specific framework was available, so generic ACMG computational-evidence calibration was used.

The non-missense SpliceAI path supports BP4 at supporting strength (maximum delta 0.022 < 0.1); PP3 is not met and is not co-applied. BP7 is not applicable to a 5′-UTR insertion.

No applicable KLLN-specific ClinGen CSPEC/VCEP or local framework was available, so the generic ACMG/AMP framework was used.

Population evidence is limited to database absence: it supports PM2 at supporting strength but does not establish BA1, BS1, or BS2.

No literature papers were identified for this population-criteria assessment, and paper_extracts.json was empty.

Met · 2

PM2 SupportingMet (supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population reference datasets. Details ▾Hide ▴
Reasoning

PM2 is met at supporting strength. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which are population reference datasets. No population allele count or frequency was identified to suggest that the variant is common in controls.

Rule
Generic ACMG/AMP PM2 supports rarity when a variant is absent or extremely rare in population databases; the available case evidence supports supporting-strength PM2, without a gene-specific refinement.
Evidence considered
  • 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.
  • The variant is an upstream noncoding insertion, and no disease-specific population threshold or penetrance model was provided; therefore PM2 is applied only at supporting strength under the generic ACMG/AMP fallback.
Still missing
  • No disease-specific maximum credible allele-frequency threshold or ancestry-specific case-control analysis was available.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMet (supporting): SpliceAI maximum delta 0.022 falls below the 0.1 BP4 threshold, predicting no significant splice impact. Details ▾Hide ▴
Reasoning

The variant is a non-missense 5′-UTR insertion. SpliceAI maximum delta score is 0.022, which is below the generic BP4 threshold (<0.1), predicting no significant splice impact.

Rule
Generic ACMG non-missense SpliceAI calibration: BP4 supporting at maximum delta <0.1; PP3 is not co-applied.
Evidence considered
  • 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.
Sources
spliceai ↗generic_acmg_combination_rules

Not met · 5 · evaluated, threshold not reached

PP3 Not met: SpliceAI maximum delta 0.022 does not exceed the >0.2 PP3 threshold. Details ▾Hide ▴
Reasoning

The variant is a non-missense 5′-UTR insertion, so the generic non-missense SpliceAI path applies. Its maximum SpliceAI delta score (0.022) does not exceed the PP3 threshold (>0.2).

Rule
Generic ACMG non-missense SpliceAI calibration: PP3 supporting at maximum delta >0.2.
Evidence considered
  • 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 PP3 only when maximum delta is >0.2.
Sources
spliceai ↗generic_acmg_combination_rules
PP5 Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to support it. Details ▾Hide ▴
Reasoning

The exact variant was not found in ClinVar, so there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion to support PP5.

Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • ClinVar exact-variant searches for NM_001126049.2:c.-535_-534insC and its genomic representations returned no match; no ClinVar submissions or variation ID were retrieved.
Sources
clinvar ↗
BA1 Not met: the variant is absent from population databases, so no allele frequency exceeds the stand-alone benign threshold. Details ▾Hide ▴
Reasoning

BA1 is not met. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no population allele frequency exceeds a stand-alone benign threshold.

Rule
Generic ACMG/AMP BA1 requires a population allele frequency high enough to establish a stand-alone benign threshold; no such frequency is observed here.
Evidence considered
  • The consolidated evidence reports the variant as absent from gnomAD v2.1.
  • The consolidated evidence reports the variant as absent from gnomAD v4.1.
  • The consolidated evidence reports the variant as absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Not met: the variant is absent from population datasets, so no allele frequency exceeds the benign threshold for the relevant disorder. Details ▾Hide ▴
Reasoning

BS1 is not met. The variant is absent from the available population datasets, so there is no allele frequency greater than expected for the relevant disorder.

Rule
Generic ACMG/AMP BS1 requires an allele frequency greater than expected for the disorder; absence from the queried population datasets does not meet BS1.
Evidence considered
  • The variant is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
  • Because no allele count or allele frequency is reported, the available data do not support an excess-frequency benign finding.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP6 Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists to support it. Details ▾Hide ▴
Reasoning

The exact variant was not found in ClinVar, so there is no exact-variant ClinVar expert-panel Benign or Likely benign assertion to support BP6.

Rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
  • ClinVar exact-variant searches for NM_001126049.2:c.-535_-534insC and its genomic representations returned no match; no ClinVar submissions or variation ID were retrieved.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 Not assessed: no de novo occurrence with confirmed maternity/paternity and absence of the variant in both parents is documented. Details ▾Hide ▴
Reasoning

No proband-level de novo observation or documented parental testing is present in the case-evidence bundle. PS2 cannot be assessed without confirmed maternity/paternity and absence of the variant in both tested parents, with appropriate consideration of phenotype and mosaicism.

Rule
Generic ACMG/AMP PS2: de novo occurrence must be established with confirmed maternity and paternity and appropriate phenotype/family evidence; no qualifying evidence is available.
Evidence considered
  • The case-evidence bundle contains no proband, parental-testing, meiosis, or de novo evidence for NM_001126049.2:c.-535_-534insC.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP criteria are therefore the fallback.
Still missing
  • Proband clinical record and variant observation are not provided.
  • Parental genotypes and testing methods/results are not provided.
  • Phenotype consistency and de novo confirmation details are not provided.
PS3 Not assessed: no validated functional assay result for this specific insertion was available. Details ▾Hide ▴
Reasoning

No validated functional assay data for NM_001126049.2:c.-535_-534insC were identified in the case evidence bundle. The variant is an upstream noncoding insertion with no variant-specific functional study, assay result, or experimental control information available; therefore PS3 cannot be assessed.

Evidence considered
  • The case summary and evidence bundle contain no variant-specific functional assay results for NM_001126049.2:c.-535_-534insC.
  • The literature pass reports zero PMIDs, and paper_extracts.json is empty; no experimental publication was available for PS3 assessment.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved, so generic ACMG/AMP criteria apply.
Still missing
  • Variant-specific functional assay demonstrating a damaging effect is unavailable.
  • Assay validation, controls, biological relevance, and reproducibility information are unavailable.
PS4 Not assessed: no case series, case-control comparison, or enrichment statistic for this exact insertion was available. Details ▾Hide ▴
Reasoning

No variant-specific affected-case series, case-control comparison, or enrichment statistic is available for this exact KLLN promoter insertion.

Rule
Generic ACMG/AMP PS4: prevalence of the variant in affected individuals is significantly increased compared with controls.
Evidence considered
  • No PMIDs were identified in the case literature packet, and paper_extracts contains no extracted paper findings for this variant.
  • No KLLN VCEP/CSPEC specification was retrieved; generic ACMG/AMP PS4 assessment requires a statistically increased prevalence in affected individuals compared with controls.
Still missing
  • Variant-specific case and control counts or a validated enrichment analysis are required.
PM3 Not assessed: no affected-proband observations, phase data, or co-occurring pathogenic alleles were identified. Details ▾Hide ▴
Reasoning

No affected-proband observations, phase data, or co-occurring pathogenic/likely pathogenic alleles were identified for this variant. Therefore, PM3 cannot be applied.

Rule
Generic ACMG/AMP PM3: apply only when the variant is observed in trans with a pathogenic or likely pathogenic variant in an affected individual; do not apply without reliable phase and affected-proband evidence.
Evidence considered
  • The case evidence bundle reports no literature PMIDs, no ClinVar record, and no family or proband-level allelic observations for NM_001126049.2:c.-535_-534insC.
  • Generic ACMG/AMP PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual, with strength determined by the number and quality of such observations; those data are absent here.
Still missing
  • Affected-proband case data with the variant are unavailable.
  • No confirmed pathogenic or likely pathogenic variant in trans, and no segregation or phase information, is available.
PM6 Not assessed: no suspected de novo occurrence without confirmed parental testing is documented. Details ▾Hide ▴
Reasoning

No suspected de novo occurrence without confirmed parental relationships or parental testing is documented. PM6 cannot be assessed from the available evidence.

Rule
Generic ACMG/AMP PM6: a suspected de novo variant without confirmation of maternity and paternity may provide supporting evidence only when the clinical and family context is documented; no qualifying evidence is available.
Evidence considered
  • The case-evidence bundle contains no suspected-de-novo, parental, maternity/paternity, or phenotype evidence for this variant.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP criteria are therefore the fallback.
Still missing
  • Clinical report of the proband and variant detection is not provided.
  • Evidence supporting de novo status despite incomplete parental confirmation is not provided.
  • Phenotype consistency and family-history context are not provided.
PP1 Not assessed: no affected relatives, familial genotypes, or phenotype-segregation data were identified. Details ▾Hide ▴
Reasoning

No affected relatives, familial genotypes, informative meioses, or phenotype-segregation data are present. Segregation evidence for PP1 cannot be assessed.

Rule
Generic ACMG/AMP PP1: cosegregation with disease in affected family members can support pathogenicity, with strength determined by the amount and informativeness of segregation; no segregation data are available.
Evidence considered
  • The case-evidence bundle contains no pedigree, affected-relative, familial-genotype, meiosis, or segregation evidence for this variant.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP criteria are therefore the fallback.
Still missing
  • Family pedigree and affected-relative phenotypes are not provided.
  • Genotypes of informative relatives are not provided.
  • Number of informative meioses and segregation results are not provided.
PP4 Not assessed: no phenotype or clinical information for the carrier was provided, so phenotype specificity cannot be evaluated. Details ▾Hide ▴
Reasoning

No phenotype, diagnostic workup, or proband-level clinical information is provided for the individual carrying this variant; phenotype specificity cannot be evaluated.

Rule
Generic ACMG/AMP PP4: the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
Evidence considered
  • No KLLN VCEP/CSPEC phenotype rule was retrieved.
  • The case bundle contains no individual phenotype or case-level clinical data for this variant.
Still missing
  • Provide the individual's phenotype and diagnostic evaluation, including assessment for alternative molecular etiologies.
BS2 Not assessed: no unaffected adult carriers or unaffected homozygotes with phenotype information were identified. Details ▾Hide ▴
Reasoning

BS2 cannot be assessed from the available evidence. No unaffected adult carriers or unaffected homozygotes/compound heterozygotes with appropriate age and phenotype information were identified.

Rule
Generic ACMG/AMP BS2 requires observation of the variant in healthy adults with an age and phenotype appropriate to exclude the relevant disease; population absence alone does not establish BS2.
Still missing
  • No clinical cohort or family data documenting unaffected adults carrying the variant were available.
BS3 Not assessed: no validated functional study demonstrating a normal effect of this variant was available. Details ▾Hide ▴
Reasoning

No validated functional assay data for NM_001126049.2:c.-535_-534insC were identified in the case evidence bundle. There is no variant-specific well-established functional study showing a normal effect with appropriate controls and biologically relevant readout; therefore BS3 cannot be assessed.

Evidence considered
  • The case summary and evidence bundle contain no variant-specific functional assay results for NM_001126049.2:c.-535_-534insC.
  • The literature pass reports zero PMIDs, and paper_extracts.json is empty; no experimental publication was available for BS3 assessment.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved, so generic ACMG/AMP criteria apply.
Still missing
  • Variant-specific functional assay demonstrating a normal effect is unavailable.
  • Assay validation, controls, biological relevance, and reproducibility information are unavailable.
BS4 Not assessed: no variant-carrying family members or informative non-segregation observations were documented. Details ▾Hide ▴
Reasoning

No family members carrying the variant, their phenotypes, or informative non-segregation observations are documented. BS4 cannot be assessed.

Rule
Generic ACMG/AMP BS4: lack of segregation in affected family members can support benignity when adequately documented and informative; no such evidence is available.
Evidence considered
  • The case-evidence bundle contains no non-segregation, variant-positive unaffected-relative, pedigree, or familial-testing evidence for this variant.
  • No applicable KLLN-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP criteria are therefore the fallback.
Still missing
  • Pedigree and phenotypes of variant-positive relatives are not provided.
  • Familial testing results are not provided.
  • Reliable assessment of affected and unaffected carriers is not possible from the available bundle.
BP2 Not assessed: no phase observations or co-occurring pathogenic variants were identified to establish a trans/cis relationship. Details ▾Hide ▴
Reasoning

No proband-level phase observations or co-occurring pathogenic/likely pathogenic variants were identified. Thus, there is no evidence to apply BP2 or to establish the required trans/cis relationship.

Rule
Generic ACMG/AMP BP2: apply only with reliable phase evidence showing the variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant; do not apply without documented allelic observations.
Evidence considered
  • The case evidence bundle contains no affected-proband observations, family studies, phase information, or co-occurring pathogenic/likely pathogenic variants for this case.
  • Generic ACMG/AMP BP2 requires reliable observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant; neither relationship is documented here.
Still missing
  • No affected or unaffected individual-level genotype data are available for phase assessment.
  • No confirmed pathogenic or likely pathogenic partner variant is documented in cis or trans.
BP5 Not assessed: no alternative causal diagnosis was documented to determine whether another finding explains the phenotype. Details ▾Hide ▴
Reasoning

No individual-level phenotype, molecular findings, or alternative causal diagnosis is available to assess whether another molecular diagnosis fully explains the observed phenotype.

Rule
Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.
Evidence considered
  • The case bundle contains no proband phenotype or other molecular diagnoses.
  • No KLLN VCEP/CSPEC specification was retrieved.
Still missing
  • Provide the individual's phenotype and complete molecular diagnostic results, including any independently explanatory pathogenic variant.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: the insertion lies in the 5' untranslated region upstream of the coding sequence, leaving the encoded protein unchanged. Details ▾Hide ▴
Reasoning

The one-base insertion is in the 5′ untranslated region (c.-535_-534), upstream of the CDS, and is predicted to leave the encoded protein unchanged. It is not a null variant or a canonical splice-site variant; therefore PVS1 is not applicable.

Rule
Generic ClinGen SVI PVS1 framework: apply only to qualifying predicted loss-of-function variants after transcript/consequence assessment.
Evidence considered
  • NM_001126049.2 places c.-535_-534insC upstream of the coding sequence (CDS c.1-c.537); the normalized protein prediction is p.(=).
  • The variant-level PVS1 assessment identifies this change as non-canonical splice, in the 'other' bucket, and states that it is outside the generic PVS1 null-variant buckets.
Sources
pvs1_variant_assessment
PS1 N/ANot applicable: this is a noncoding 5' insertion with no amino-acid change (p.(=)), so there is no missense to compare with known pathogenic changes. Details ▾Hide ▴
Reasoning

PS1 is not applicable because NM_001126049.2:c.-535_-534insC is an upstream-of-CDS noncoding insertion with predicted protein consequence NP_001119521.1:p.(=), not a missense substitution with an amino-acid change that could be compared with a known same-amino-acid change.

Rule
PS1 applies only when a different nucleotide change produces the same amino-acid change; this upstream noncoding insertion has no missense amino-acid change.
Evidence considered
  • case_summary.json identifies the variant as NM_001126049.2:c.-535_-534insC and the normalized protein consequence as NP_001119521.1:p.(=).
  • prefetch.json places c.-535_-534insC upstream of the CDS (outside_cds=upstream) and reports the predicted protein consequence as p.(=).
  • No governing KLLN-specific CSPEC/VCEP framework was available; generic ACMG/AMP interpretation was therefore used only for applicability.
  • No literature records were available in literature_pass.json, and paper_extracts.json is empty.
PM1 N/ANot applicable: the variant is upstream of the coding sequence, so no amino-acid residue exists to evaluate against functional domains or hotspots. Details ▾Hide ▴
Reasoning

PM1 is not applicable because the variant is upstream of the coding sequence and has no affected amino-acid residue to evaluate against critical functional domains or hotspots. vcep_materials.json contains no KLLN domain-table entries.

Rule
PM1 requires a missense variant affecting a residue within a well-established critical functional domain or hotspot; no coding residue is affected here.
Evidence considered
  • prefetch.json reports c.-535_-534insC as outside_cds=upstream and predicts NP_001119521.1:p.(=), so no coding residue is affected.
  • vcep_materials.json reports no applicable CSPEC/VCEP and an empty domain_tables object; therefore there is no authoritative KLLN critical-domain entry to apply.
  • No literature records were available in literature_pass.json, and paper_extracts.json is empty.
PM4 N/ANot applicable: the 5' untranslated region insertion leaves the protein unchanged (p.(=)) and does not alter protein length. Details ▾Hide ▴
Reasoning

PM4 requires a protein-length change from an in-frame deletion/insertion or stop-loss. This 5′ UTR insertion is upstream of the CDS and has a predicted protein consequence of p.(=), so it does not alter protein length.

Rule
Generic ACMG/AMP PM4: protein-length change caused by an in-frame deletion/insertion in a non-repeat region or by stop-loss.
Evidence considered
  • NM_001126049.2 places c.-535_-534insC upstream of the coding sequence (CDS c.1-c.537); the normalized protein prediction is p.(=).
Sources
pvs1_variant_assessment
PM5 N/ANot applicable: not a missense variant, so there is no amino-acid residue at which an alternate pathogenic missense could be compared. Details ▾Hide ▴
Reasoning

PM5 is not applicable because this is not a missense variant and has no affected amino-acid residue at which an alternate pathogenic missense change could be compared.

Rule
PM5 requires a novel missense change at a residue where a different missense change is established as pathogenic; this variant does not alter a coding amino-acid residue.
Evidence considered
  • case_summary.json reports the normalized protein consequence as NP_001119521.1:p.(=) and variant_class as null.
  • prefetch.json reports the insertion at c.-535_-534 upstream of the CDS and a predicted synonymous protein consequence.
  • pm5_candidates.json summary reports no eligible classic PM5 search because same-residue PM5 semantics cannot be established for this variant.
PP2 N/ANot applicable: intended for missense variants in genes where missense is a common disease mechanism; this is a noncoding insertion. Details ▾Hide ▴
Reasoning

PP2 is not applicable because it is intended for missense variants in genes where missense variation is a common disease mechanism; this variant is an upstream noncoding insertion with no missense consequence.

Rule
PP2 is applicable only to missense variants in an appropriate missense-disease-mechanism context; the present variant is noncoding and does not produce a missense change.
Evidence considered
  • case_summary.json identifies the normalized protein consequence as NP_001119521.1:p.(=), not a missense change.
  • prefetch.json places the insertion upstream of the CDS (outside_cds=upstream).
BP1 N/ANot applicable: intended for missense variants in genes where truncation is the established mechanism; this is a noncoding insertion. Details ▾Hide ▴
Reasoning

BP1 is not applicable because it is intended for missense variants in genes where truncating variants are the established disease mechanism; this variant is an upstream noncoding insertion and is not a missense variant.

Rule
BP1 is applicable only to missense variants in a gene with an established truncating-variant disease mechanism; the present variant is noncoding and has no missense consequence.
Evidence considered
  • case_summary.json identifies the normalized protein consequence as NP_001119521.1:p.(=), not a missense change.
  • prefetch.json places the insertion upstream of the CDS (outside_cds=upstream).
BP3 N/ANot applicable: applies to in-frame coding indels in repeat regions; this 5' insertion leaves the protein unchanged (p.(=)). Details ▾Hide ▴
Reasoning

BP3 concerns in-frame coding deletions/insertions within a repetitive region lacking known function. This is a 5′ UTR insertion with predicted p.(=), not an in-frame protein alteration; repeat-region assessment is therefore not relevant.

Rule
Generic ACMG/AMP BP3: in-frame deletion/insertion in a repetitive region without a known function.
Evidence considered
  • NM_001126049.2 places c.-535_-534insC upstream of the coding sequence (CDS c.1-c.537); the normalized protein prediction is p.(=).
Sources
pvs1_variant_assessment
BP7 N/ANot applicable: reserved for synonymous coding variants; this is a 5' untranslated region insertion, not a synonymous change. Details ▾Hide ▴
Reasoning

BP7 is a synonymous-variant criterion. NM_001126049.2:c.-535_-534insC is an upstream 5′-UTR insertion, not a synonymous coding variant.

Rule
BP7 is not applicable to this noncoding 5′-UTR insertion.
Evidence considered
  • Variant normalization places c.-535_-534insC upstream of the coding sequence; the predicted protein sequence is unchanged.

Identifiers

Gene
KLLN
Transcript
NM_001126049.2
Coding (HGVS c.)
NM_001126049.2:c.-535_-534insC
Protein (HGVS p.)
NP_001119521.1:p.?
GRCh38
chr10:87863021 A>AG
GRCh37
chr10:89622778 A>AG
Location and type
Exon 1 · unknown

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -218 bp
0.003
SpliceAI acceptor gainat -15 bp
0.014
SpliceAI donor lossat +183 bp
0.022
SpliceAI donor gainat -448 bp
0.007
Pangolin splice lossmagnitude shown
-0.011
Pangolin splice gain
0.016

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMet (supporting): SpliceAI maximum delta 0.022 falls below the 0.1 BP4 threshold, predicting no significant splice impact. Details ▾Hide ▴
Reasoning

The variant is a non-missense 5′-UTR insertion. SpliceAI maximum delta score is 0.022, which is below the generic BP4 threshold (<0.1), predicting no significant splice impact.

Rule
Generic ACMG non-missense SpliceAI calibration: BP4 supporting at maximum delta <0.1; PP3 is not co-applied.
Evidence considered
  • 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.
Sources
spliceai ↗generic_acmg_combination_rules
PP3 Not met: SpliceAI maximum delta 0.022 does not exceed the >0.2 PP3 threshold. Details ▾Hide ▴
Reasoning

The variant is a non-missense 5′-UTR insertion, so the generic non-missense SpliceAI path applies. Its maximum SpliceAI delta score (0.022) does not exceed the PP3 threshold (>0.2).

Rule
Generic ACMG non-missense SpliceAI calibration: PP3 supporting at maximum delta >0.2.
Evidence considered
  • 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 PP3 only when maximum delta is >0.2.
Sources
spliceai ↗generic_acmg_combination_rules
BP7 N/ANot applicable: reserved for synonymous coding variants; this is a 5' untranslated region insertion, not a synonymous change. Details ▾Hide ▴
Reasoning

BP7 is a synonymous-variant criterion. NM_001126049.2:c.-535_-534insC is an upstream 5′-UTR insertion, not a synonymous coding variant.

Rule
BP7 is not applicable to this noncoding 5′-UTR insertion.
Evidence considered
  • Variant normalization places c.-535_-534insC upstream of the coding sequence; the predicted protein sequence is unchanged.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.022 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC 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

Absent from gnomAD v4.1.

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 = 0.02).

Somatic

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