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KLLNc.-694T>GUncertain significance
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Variant interpretation report

KLLN c.-694T>G, p.?

NM_001126049.2:c.-694T>G NP_001119521.1:p.? View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About KLLN

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 185,458 alleles

gnomAD v4.1: 2 / 185,458 alleles. Recorded AF 1.07841e-05. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
SpliceAI score
0.080 maximum delta

Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 4 not met · 12 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 1

PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2 is used for variants absent or at very low frequency in population databases.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AF 1.07841e-05
  • Highest subpopulation AF 7.87154e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

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. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines supporting a deleterious effect.
Evidence considered
  • SpliceAI max delta score 0.08
  • REVEL not found
  • BayesDel not found
Still missing
  • No validated predictor result was identified for promoter-specific regulatory impact.
Sources
spliceai ↗
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. Details ▾Hide ▴
Rule
BA1 requires allele frequency above the stand-alone benign threshold.
Evidence considered
  • Overall AF 1.07841e-05
  • Highest population AF 7.87154e-05
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Rule
BS1 requires allele frequency greater than expected for the disorder.
Evidence considered
  • Overall AF 1.07841e-05
  • Highest population AF 7.87154e-05
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Rule
BP4 requires multiple computational lines supporting no impact.
Evidence considered
  • SpliceAI max delta score 0.08
Still missing
  • No validated computational assessment of promoter-specific regulatory impact was identified.
Sources
spliceai ↗

Not assessed · 12 · no assessment recorded

PS2 No confirmed de novo occurrence was identified for this variant. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history.
Evidence considered
  • No de novo evidence located
Still missing
  • No trio-based report with confirmed maternity and paternity was identified.
PS3 No well-established functional study was identified for this exact variant, so a damaging functional effect cannot be concluded. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies showing a damaging effect.
Evidence considered
  • No exact functional data located
Still missing
  • No variant-specific promoter
  • expression
  • or other functional assay was identified.
PS4 No case-control enrichment or affected-individual count data were identified for this variant. Details ▾Hide ▴
Rule
PS4 requires increased prevalence in affected individuals compared with controls.
Evidence considered
  • ClinVar absent
  • Very low population frequency alone does not establish enrichment
Still missing
  • No published case series or statistical enrichment data were identified.
Sources
clinvar ↗gnomad_v4 ↗
PM1 Available evidence does not identify c.-694 as part of a well-established mutational hotspot or a critical functional region without benign variation. Details ▾Hide ▴
Rule
PM1 requires a mutational hotspot or critical functional domain with low benign variation.
Evidence considered
  • No hotspot or critical-region evidence located
Still missing
  • No validated critical promoter element or pathogenic variant cluster was identified at this position.
PM6 No assumed de novo report was identified for this variant. Details ▾Hide ▴
Rule
PM6 requires assumed de novo occurrence without confirmed parentage.
Evidence considered
  • No assumed de novo evidence located
Still missing
  • No proband-only report with unaffected parents was identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Evidence considered
  • No segregation evidence located
Still missing
  • No family study showing cosegregation with disease was identified.
PP4 No phenotype or family history information was provided to assess whether the clinical presentation is highly specific for a KLLN-related disorder. Details ▾Hide ▴
Rule
PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
  • No phenotype-specific evidence available
Still missing
  • Phenotypic details are needed.
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. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adults in a context inconsistent with disease penetrance.
Evidence considered
  • 2/185458 alleles
  • 0 homozygotes
Still missing
  • More robust healthy adult observation data would be needed.
Sources
gnomad_v4 ↗
BS3 No well-established functional study was identified showing normal function for this exact variant. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
  • No benign functional data located
Still missing
  • No variant-specific benign functional assay was identified.
BS4 No nonsegregation data were identified for this variant. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in affected family members.
Evidence considered
  • No nonsegregation evidence located
Still missing
  • No family study showing lack of segregation with disease was identified.
BP2 No co-occurrence or phase data were identified for this variant. Details ▾Hide ▴
Rule
BP2 requires specific co-occurrence or phase evidence.
Evidence considered
  • No co-occurrence evidence located
Still missing
  • No report was identified showing this variant in trans with a pathogenic variant or in cis in a context supporting BP2.
BP5 No alternate molecular explanation for the phenotype was provided, so this criterion cannot be assessed. Details ▾Hide ▴
Rule
BP5 requires a well-established alternate molecular basis for disease.
Evidence considered
  • No alternate-diagnosis data available
Still missing
  • Phenotype and other molecular findings would be needed.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AKLLN 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. Details ▾Hide ▴
Rule
Generic PVS1 fallback is limited to established null-variant categories.
Evidence considered
  • Gene-level loss-of-function mechanism is supported for KLLN.
  • Variant falls outside generic PVS1 null-variant buckets.
Still missing
  • No variant-specific evidence was identified showing a null-equivalent effect on transcription or transcript production.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/AThis is a noncoding upstream variant with no defined amino acid substitution, so same-amino-acid-change logic does not apply. Details ▾Hide ▴
Rule
PS1 applies to alternate nucleotide changes producing the same amino acid change.
Evidence considered
  • Protein consequence is p.?
PM3 N/ANo recessive disease framework or biallelic KLLN disease evidence was identified for this variant, so PM3 is not applicable. Details ▾Hide ▴
Rule
PM3 applies to recessive disorders with pathogenic variants detected in trans.
Evidence considered
  • No recessive or in-trans disease evidence located
PM4 N/AThis variant does not change protein length and is not an in-frame insertion or deletion. Details ▾Hide ▴
Rule
PM4 applies to protein length changes from in-frame indels or stop-loss variants.
Evidence considered
  • Noncoding upstream substitution
PM5 N/AThis is not a missense variant, and same-residue missense comparator logic does not apply. Details ▾Hide ▴
Rule
PM5 applies to a novel missense change at a residue with a different pathogenic missense change.
Evidence considered
  • No missense residue context available
  • PM5 candidate search marked not applicable
Sources
pm5_candidates
PP2 N/AThis criterion is intended for selected missense variants and does not apply to an upstream noncoding substitution. Details ▾Hide ▴
Rule
PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism.
Evidence considered
  • Noncoding upstream variant
PP5 N/ANo reputable-source pathogenic assertion was identified, and this criterion is not used here without primary supporting evidence. Details ▾Hide ▴
Rule
PP5 is not used without primary supporting evidence.
Evidence considered
  • ClinVar absent
Sources
clinvar ↗
BP1 N/AThis criterion applies to selected missense variants and does not apply to an upstream noncoding substitution. Details ▾Hide ▴
Rule
BP1 applies to missense variants in genes where truncating variants are primarily responsible for disease.
Evidence considered
  • Noncoding upstream variant
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Rule
BP3 applies to certain in-frame indels in repetitive regions without known function.
Evidence considered
  • Single-nucleotide upstream substitution
BP6 N/ANo reputable-source benign assertion was identified, and this criterion is not used here without primary supporting evidence. Details ▾Hide ▴
Rule
BP6 is not used without primary supporting evidence.
Evidence considered
  • ClinVar absent
Sources
clinvar ↗
BP7 N/AThis variant is not a synonymous or intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splice impact and low conservation impact.
Evidence considered
  • Upstream noncoding substitution
Sources
spliceai ↗

Identifiers

Gene
KLLN
Transcript
NM_001126049.2
Coding (HGVS c.)
NM_001126049.2:c.-694T>G
Protein (HGVS p.)
NP_001119521.1:p.?
GRCh38
chr10:87863181 A>C
GRCh37
chr10:89622938 A>C

Gene diagram

Every interpreted variant in KLLN, mapped onto the exon structure of NM_001126049.2. Select a row to find it on the plot.

KLLNNM_001126049.2
Fetching transcript structure from UCSC…
gnomAD v4.1 2 / 185,458 alleles AF 1.08e-05 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.1e-05 · 2 / 185,458 alleles · 0 hom
European (Finnish)2 / 25,408 7.9e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

SpliceAI acceptor lossat +124 bp
0.000
SpliceAI acceptor gainat -175 bp
0.010
SpliceAI donor lossat +298 bp
0.010
SpliceAI donor gainat +23 bp
0.080
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.040

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

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. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines supporting a deleterious effect.
Evidence considered
  • SpliceAI max delta score 0.08
  • REVEL not found
  • BayesDel not found
Still missing
  • No validated predictor result was identified for promoter-specific regulatory impact.
Sources
spliceai ↗
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. Details ▾Hide ▴
Rule
BP4 requires multiple computational lines supporting no impact.
Evidence considered
  • SpliceAI max delta score 0.08
Still missing
  • No validated computational assessment of promoter-specific regulatory impact was identified.
Sources
spliceai ↗
BP7 N/AThis variant is not a synonymous or intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splice impact and low conservation impact.
Evidence considered
  • Upstream noncoding substitution
Sources
spliceai ↗

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 185,458 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.080 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).