Variant classification summary

NM_001126049.2:c.136T>G

KLLN · NP_001119521.1:p.(Phe46Val) · NM_001126049.2

GRCh37: chr10:89622109 A>C · GRCh38: chr10:87862352 A>C

Gene: KLLN Transcript: NM_001126049.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KLLN

Transcript

NM_001126049.2

Protein

NP_001119521.1:p.(Phe46Val)

gnomAD AF

8.382035106542114e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD frequencies are below 0.0001.

2

BP4 supporting: REVEL 0.124 is below the 0.29 threshold.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting pathogenic criterion and one supporting benign criterion are conflicting and therefore yield VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no verified pathogenic alternate nucleotide change producing p.Phe46Val at residue 46 was supplied.	clinvar
PS2	Not assessed	Not assessed: no documented de novo observation with confirmed maternity and paternity, disease-consistent proband phenotype, and absent family history.
PS3	Not assessed	Not assessed: no variant-specific, validated in vitro or in vivo assay evidence established a damaging effect for KLLN p.Phe46Val.
PS4	Not assessed	Not assessed: no case-control odds ratio or relative risk with a confidence interval excluding 1.0 is available for this variant.
PM1	Not assessed	Not assessed: no authoritative critical-domain annotation covers KLLN F46, and no statistically significant F46 hotspot was reported.
PM2	Met	Met at supporting strength: gnomAD v4.1 overall AF is 8.38204e-06, below the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic partner, inheritance model, or parental/offspring phase testing is documented.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at KLLN residue 46 was verified as pathogenic.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no documented assumed-de-novo observation or parental testing information is available for this variant.
PP1	Not assessed	Not assessed: zero documented affected relatives or informative meioses are available to evaluate co-segregation.
PP2	Not assessed	Not assessed: KLLN loss of function is supported, but no gene-wide benign-missense rate or common-missense-mechanism evidence was supplied.	pvs1_gene_context
PP3	Not met	Not met: missense REVEL 0.124 is below the >=0.644 generic PP3 supporting threshold.	revel
PP4	Not assessed	Not assessed: patient phenotype and family history sufficient to demonstrate a highly specific single-etiology disease are unavailable.
PP5	Not assessed	Not assessed: the exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification available.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 8.78194e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the maximum observed allele frequency is 8.78194e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no qualifying healthy-adult, age, phenotype, or penetrance evidence.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific, validated in vitro or in vivo assay evidence demonstrated no damaging effect on KLLN p.Phe46Val function or splicing.
BS4	Not assessed	Not assessed: no affected family members with variant-negative testing are documented to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: KLLN loss of function is supported, but a primarily truncating disease-variant spectrum was not established.	pvs1_gene_context
BP2	Not assessed	Not assessed: no pathogenic partner or phase observation demonstrates either trans occurrence in a fully penetrant dominant disorder or cis occurrence in any inheritance pattern.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: missense REVEL 0.124 meets the <=0.29 generic BP4 supporting threshold.	revel
BP5	Not assessed	Not assessed: no case evidence documents an alternate molecular basis for the patient's disease.
BP6	Not assessed	Not assessed: the exact variant has no ClinVar expert-panel Benign or Likely benign classification available.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.