NM_001126049.2:c.-694T>G

KLLN · NP_001119521.1:p.? · NM_001126049.2

GRCh37: chr10:89622938 A>C · GRCh38: chr10:87863181 A>C

Gene: KLLN Transcript: NM_001126049.2

Final call

VUS

PM2 supporting

Variant details

Gene

KLLN

Transcript

NM_001126049.2

Protein

NP_001119521.1:p.?

gnomAD AF

1.078411284495681e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The KLLN c.-694T>G (NP_001119521.1:p.?) variant has not been reported in ClinVar.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	KLLN loss of function is an established disease mechanism, but this upstream c.-694T>G change is not a nonsense, frameshift, or canonical +/-1,2 splice variant, so the generic PVS1 framework does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This is a noncoding upstream variant with no defined amino acid substitution, so same-amino-acid-change logic does not apply.
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant.
PS3	Not assessed	No well-established functional study was identified for this exact variant, so a damaging functional effect cannot be concluded.
PS4	Not assessed	No case-control enrichment or affected-individual count data were identified for this variant.	clinvar gnomad_v4
PM1	Not assessed	Available evidence does not identify c.-694 as part of a well-established mutational hotspot or a critical functional region without benign variation.
PM2	Met	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 gnomad_v4
PM3	N/A	No recessive disease framework or biallelic KLLN disease evidence was identified for this variant, so PM3 is not applicable.
PM4	N/A	This variant does not change protein length and is not an in-frame insertion or deletion.
PM5	N/A	This is not a missense variant, and same-residue missense comparator logic does not apply.	pm5_candidates
PM6	Not assessed	No assumed de novo report was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	This criterion is intended for selected missense variants and does not apply to an upstream noncoding substitution.
PP3	Not met	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.	spliceai
PP4	Not assessed	No phenotype or family history information was provided to assess whether the clinical presentation is highly specific for a KLLN-related disorder.
PP5	N/A	No reputable-source pathogenic assertion was identified, and this criterion is not used here without primary supporting evidence.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing normal function for this exact variant.
BS4	Not assessed	No nonsegregation data were identified for this variant.
BP1	N/A	This criterion applies to selected missense variants and does not apply to an upstream noncoding substitution.
BP2	Not assessed	No co-occurrence or phase data were identified for this variant.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region.
BP4	Not met	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.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided, so this criterion cannot be assessed.
BP6	N/A	No reputable-source benign assertion was identified, and this criterion is not used here without primary supporting evidence.	clinvar
BP7	N/A	This variant is not a synonymous or intronic change, so BP7 does not apply.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.