Variant classification summary

NM_001126049.2:c.-535_-534insC

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

GRCh37: chr10:89622778 A>AG · GRCh38: chr10:87863021 A>AG

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.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the 5' untranslated region insertion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population reference datasets.

2

BP4 (Supporting): SpliceAI maximum delta score 0.022 is below the 0.1 threshold, predicting no significant splice impact.

3

Overall classification: VUS - the conflicting PM2 (supporting) and BP4 (supporting) evidence meets no ACMG/AMP 2015 Pathogenic or Benign combination threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, PM2 supporting plus BP4 supporting is a conflicting one-supporting-pathogenic/one-supporting-benign combination that defaults to 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: the insertion lies in the 5' untranslated region upstream of the coding sequence, leaving the encoded protein unchanged.	pvs1_variant_assessment
PS1	N/A	Not applicable: this is a noncoding 5' insertion with no amino-acid change (p.(=)), so there is no missense to compare with known pathogenic changes.
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed maternity/paternity and absence of the variant in both parents is documented.
PS3	Not assessed	Not assessed: no validated functional assay result for this specific insertion was available.
PS4	Not assessed	Not assessed: no case series, case-control comparison, or enrichment statistic for this exact insertion was available.
PM1	N/A	Not applicable: the variant is upstream of the coding sequence, so no amino-acid residue exists to evaluate against functional domains or hotspots.
PM2	Met	Met (supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population reference datasets.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations, phase data, or co-occurring pathogenic alleles were identified.
PM4	N/A	Not applicable: the 5' untranslated region insertion leaves the protein unchanged (p.(=)) and does not alter protein length.	pvs1_variant_assessment
PM5	N/A	Not applicable: not a missense variant, so there is no amino-acid residue at which an alternate pathogenic missense could be compared.
PM6	Not assessed	Not assessed: no suspected de novo occurrence without confirmed parental testing is documented.
PP1	Not assessed	Not assessed: no affected relatives, familial genotypes, or phenotype-segregation data were identified.
PP2	N/A	Not applicable: intended for missense variants in genes where missense is a common disease mechanism; this is a noncoding insertion.
PP3	Not met	Not met: SpliceAI maximum delta 0.022 does not exceed the >0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype or clinical information for the carrier was provided, so phenotype specificity cannot be evaluated.
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists to support it.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency exceeds the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population datasets, so no allele frequency exceeds the benign threshold for the relevant disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no unaffected adult carriers or unaffected homozygotes with phenotype information were identified.
BS3	Not assessed	Not assessed: no validated functional study demonstrating a normal effect of this variant was available.
BS4	Not assessed	Not assessed: no variant-carrying family members or informative non-segregation observations were documented.
BP1	N/A	Not applicable: intended for missense variants in genes where truncation is the established mechanism; this is a noncoding insertion.
BP2	Not assessed	Not assessed: no phase observations or co-occurring pathogenic variants were identified to establish a trans/cis relationship.
BP3	N/A	Not applicable: applies to in-frame coding indels in repeat regions; this 5' insertion leaves the protein unchanged (p.(=)).	pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI maximum delta 0.022 falls below the 0.1 BP4 threshold, predicting no significant splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternative causal diagnosis was documented to determine whether another finding explains the phenotype.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists to support it.	clinvar
BP7	N/A	Not applicable: reserved for synonymous coding variants; this is a 5' untranslated region insertion, not a synonymous change.

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