Classification rationale

PM2 BP4 VUS

KLLN c.136T>G missense · exon 1

PM2 supporting: gnomAD frequencies are below 0.0001. BP4 supporting: REVEL 0.124 is below the 0.29 threshold.

PM2 + BP4 → VUS

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 · 2 applied · 22 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 overall AF is 8.38204e-06, below the generic PM2 threshold of 0.0001.

Generic ACMG/AMP PM2 definition and supplied SVI supporting threshold: AF <=0.0001; the threshold is identified in the case data as the ClinGen SVI 2020 recommendation to downgrade PM2 to supporting (PMID:25741868).gnomAD v2.1 exomes report AF 1.29808e-05 (2/154074 alleles; zero homozygotes), with highest subgroup AF 8.78194e-05 in South Asian individuals.gnomAD v4.1 reports AF 8.38204e-06 (13/1550936 alleles; zero homozygotes), with highest subgroup AF 5.94983e-05 in South Asian individuals; all values are <=0.0001.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Met, supporting: missense REVEL 0.124 meets the <=0.29 generic BP4 supporting threshold.

NM_001126049.2:c.136T>G is an exonic missense variant producing NP_001119521.1:p.(Phe46Val), so only REVEL is applicable for this criterion.The local REVEL lookup reports 0.124 for the variant (source_registry key: revel).The supplied generic calibration assigns BP4 supporting at REVEL <= 0.29; this threshold is from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).

Assessed · not applied · 3 not met · 19 not assessed

Pathogenic

PS1 Not assessed: no verified pathogenic alternate nucleotide change producing p.Phe46Val at residue 46 was supplied.

PS2 Not assessed: no documented de novo observation with confirmed maternity and paternity, disease-consistent proband phenotype, and absent family history.

PS3 Not assessed: no variant-specific, validated in vitro or in vivo assay evidence established a damaging effect for KLLN p.Phe46Val.

PS4 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: no authoritative critical-domain annotation covers KLLN F46, and no statistically significant F46 hotspot was reported.

PM3 Not assessed: no affected-proband observation, pathogenic partner, inheritance model, or parental/offspring phase testing is documented.

PM5 Not assessed: no different missense change at KLLN residue 46 was verified as pathogenic.

PM6 Not assessed: no documented assumed-de-novo observation or parental testing information is available for this variant.

PP1 Not assessed: zero documented affected relatives or informative meioses are available to evaluate co-segregation.

PP2 Not assessed: KLLN loss of function is supported, but no gene-wide benign-missense rate or common-missense-mechanism evidence was supplied.

PP3 Not met: missense REVEL 0.124 is below the >=0.644 generic PP3 supporting threshold.

PP4 Not assessed: patient phenotype and family history sufficient to demonstrate a highly specific single-etiology disease are unavailable.

PP5 Not assessed: the exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification available.

Benign

BA1 Not met: the highest observed allele frequency is 8.78194e-05, far below the generic BA1 threshold of 0.05.

BS1 Not met: the maximum observed allele frequency is 8.78194e-05, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD reports zero homozygotes but provides no qualifying healthy-adult, age, phenotype, or penetrance evidence.

BS3 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: no affected family members with variant-negative testing are documented to demonstrate lack of segregation.

BP1 Not assessed: KLLN loss of function is supported, but a primarily truncating disease-variant spectrum was not established.

BP2 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.

BP5 Not assessed: no case evidence documents an alternate molecular basis for the patient's disease.

BP6 Not assessed: the exact variant has no ClinVar expert-panel Benign or Likely benign classification available.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 8.38204e-06; MAF= 0.00084%, 13/1550936 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 5.94983e-05; MAF= 0.00595%, 5/84036 alleles, homozygotes = 0); grpmax FAF= 2.338e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.29808e-05; MAF= 0.00130%, 2/154074 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.78194e-05; MAF= 0.00878%, 2/22774 alleles, homozygotes = 0); grpmax FAF= 1.552e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00084% · 13 / 1,550,936
0 hom · FAF 0.0023%

South Asian 5 / 84,036	0.0059%
European (non-Finnish) 8 / 1,146,824	0.0007%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0013% · 2 / 154,074
0 hom · FAF 0.0016%

South Asian

2 / 22,774

0.0088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.124. BayesDel score = -0.246326.

SpliceAI ↗

Functional No data

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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