Classification rationale

PM2 VUS

KLLN c.-694T>G

The KLLN c.-694T>G (NP_001119521.1:p.?) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/185458 alleles; AF 0.00108%; highest observed population AF 0.00787% in Finnish), supporting rarity and meeting PM2 at supporting strength while remaining far below benign frequency thresholds.² SpliceAI predicts no significant splice impact for this variant (max delta score 0.08), but no validated computational evidence was identified to determine whether this upstream change has a damaging or benign regulatory effect.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 · 1 applied · 16 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/185458 alleles; AF 0.00108%; highest observed population AF 0.00787% in Finnish), which is below the 0.1% rarity threshold used here and supports rarity.

gnomAD v2.1 absentgnomAD v4.1 total AF 1.07841e-05Highest subpopulation AF 7.87154e-05

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 12 not assessed

Pathogenic

PS2 No confirmed de novo occurrence was identified for this variant.

PS3 No well-established functional study was identified for this exact variant, so a damaging functional effect cannot be concluded.

PS4 No case-control enrichment or affected-individual count data were identified for this variant.

PM1 Available evidence does not identify c.-694 as part of a well-established mutational hotspot or a critical functional region without benign variation.

PM6 No assumed de novo report was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.08), and no REVEL, BayesDel, or other validated computational evidence was identified to support a damaging effect on this upstream regulatory change.

PP4 No phenotype or family history information was provided to assess whether the clinical presentation is highly specific for a KLLN-related disorder.

Benign

BA1 The observed population frequency is well below the benign stand-alone threshold of 1%: gnomAD v4.1 shows AF 0.00108% overall and 0.00787% in the highest observed population.

BS1 The population frequency is below the benign strong threshold of 0.3%: gnomAD v4.1 shows AF 0.00108% overall and 0.00787% in the highest observed population.

BS2 This variant has only two alleles in gnomAD v4.1 and no homozygotes, which does not provide enough evidence that it is observed in healthy adults at a rate expected to argue against pathogenicity.

BS3 No well-established functional study was identified showing normal function for this exact variant.

BS4 No nonsegregation data were identified for this variant.

BP2 No co-occurrence or phase data were identified for this variant.

BP4 SpliceAI predicts no significant splice impact (max delta score 0.08), but this isolated splicing result does not establish that an upstream regulatory variant is benign, so benign computational evidence is insufficient.

BP5 No alternate molecular explanation for the phenotype was provided, so this criterion cannot be assessed.

N/A · 11 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.07841e-05; MAF= 0.00108%, 2/185458 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 7.87154e-05; MAF= 0.00787%, 2/25408 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0011% · 2 / 185,458
0 hom

European (Finnish)

2 / 25,408

0.0079%

+ 9 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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