LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-13
Case ID: NM_001202543.1_c.2598_2606dupTGGCAGCGG_20260813_202936
Framework: ACMG/AMP 2015
Variant classification summary

NM_001202543.1:c.2598_2606dupTGGCAGCGG

CUX1  · NP_001189472.1:p.(Ser868_Gly870dup)  · NM_001202543.1
GRCh37: chr7:101845133 G>GGGCAGCGGT  ·  GRCh38: chr7:102201853 G>GGGCAGCGGT
Gene: CUX1 Transcript: NM_001202543.1
Final call
Benign
BA1 stand-alone benign BP3 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
CUX1
Transcript
NM_001202543.1
Protein
NP_001189472.1:p.(Ser868_Gly870dup)
gnomAD AF
0.0010462520252538462 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BA1 (Stand-alone): highest observed population allele frequency 1.99% in African/African American (gnomAD v4.1) exceeds the 1% BA1 threshold, corroborated by gnomAD v2.1 (1.77%) and gnomAD-Canada (2.55%).
2
BP3 (Supporting): in-frame 9-bp/3-amino-acid duplication p.(Ser868_Gly870dup) lies in a tandem SGG repeat region without known function, outside all CUT/homeodomain DNA-binding domains, with no predicted splice impact (SpliceAI max delta 0.006).
3
Overall classification: Benign, per the generic ACMG/AMP 2015 combination rule '(1 BA1) -> Benign'; no pathogenic criterion is met.
Final determination: Under the generic ACMG/AMP 2015 fallback combination rules, a single stand-alone benign criterion (BA1: highest observed population AF 1.99% > 1% threshold) yields a Benign classification, with supporting BP3 (in-frame repeat-region indel without known function) adding further benign evidence and no met pathogenic criterion to conflict.
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: this is an in-frame duplication, not a null variant class such as nonsense, frameshift, or canonical splice disruption.
pvs1_generic_framework generic_acmg_combination_rules
PS1 N/A Not applicable: no single altered amino acid exists to compare, since the change is a 3-amino-acid in-frame duplication.
generic_acmg_combination_rules
PS2 Not assessed Not assessed: no proband-parent trio or parental-confirmation data for this variant was available.
generic_acmg_combination_rules
PS3 Not assessed Not assessed: no well-established functional assay evidence for this variant was available.
oncokb clinvar generic_acmg_combination_rules
PS4 Not assessed Not assessed: no case-control or case-series evidence exists; the only observation is a single somatic COSMIC entry.
gnomad_v4 gnomad_v2 generic_acmg_combination_rules
PM1 N/A Not applicable: PM1 requires a missense change; this in-frame duplication has no single altered residue to evaluate.
generic_acmg_combination_rules
PM2 Not met Not met: gnomAD v4.1 overall allele frequency 0.105% exceeds the 0.1% PM2 ceiling (1.99% in African/African American).
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3 Not met Not met: no trans observation with a pathogenic variant and no recessive disease model; 12 homozygotes exist in gnomAD v4.1.
generic_acmg_combination_rules pvs1_gene_context gnomad_v4 gnomad_v2 gnomad_canada clinvar
PM4 N/A Not applicable: the duplicated SGG unit is a perfect tandem repeat in a low-complexity region, which PM4 explicitly excludes.
generic_acmg_combination_rules
PM5 N/A Not applicable: no missense change exists at this residue to compare against a pathogenic missense at the same position.
generic_acmg_combination_rules
PM6 Not assessed Not assessed: no proband-parent testing data exists, so an assumed de novo occurrence cannot be evaluated.
generic_acmg_combination_rules
PP1 Not assessed Not assessed: no pedigree, affected-family-member genotyping, or segregation data for this variant was available.
generic_acmg_combination_rules
PP2 N/A Not applicable: no missense change is present, so the gene's missense-constraint properties are not relevant.
generic_acmg_combination_rules
PP3 Not met Not met: SpliceAI max delta 0.006 predicts no splice impact, far below the 0.2 cutoff; missense predictors do not apply.
spliceai generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype or family-history data, and no publication reports this exact variant in an affected patient.
generic_acmg_combination_rules clinvar
PP5 Not met Not met: no ClinVar expert-panel (3-star) classification exists; the sole submission is a 0-star laboratory Benign label.
clinvar generic_acmg_combination_rules
BA1 Met Met (stand-alone benign): highest population allele frequency 1.99% in African/African American (gnomAD v4.1) exceeds the 1% BA1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1 Not met Not met: the 1.99% frequency exceeds both frequency thresholds but triggers BA1 instead, since BS1 and BA1 are mutually exclusive.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2 Not met Not met: 12 homozygotes in gnomAD v4.1, but no established penetrance or inheritance model for CUX1-related germline disease.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3 Not assessed Not assessed: no validated functional study showing no damaging effect on protein function or splicing was available.
oncokb clinvar generic_acmg_combination_rules
BS4 Not assessed Not assessed: no familial segregation testing data for this variant was available.
generic_acmg_combination_rules
BP1 N/A Not applicable: BP1 applies to missense variants; this is an in-frame duplication, not a missense change.
generic_acmg_combination_rules
BP2 Not met Not met: no observation of this variant in trans or cis with a pathogenic variant exists.
generic_acmg_combination_rules pvs1_gene_context clinvar
BP3 Met Met (supporting benign): in-frame 3-amino-acid duplication in a tandem SGG repeat region without known function.
generic_acmg_combination_rules oncokb spliceai
BP4 Not met Not met: a single SpliceAI line (max delta 0.006) does not satisfy BP4's multiple-lines-of-evidence requirement.
spliceai generic_acmg_combination_rules
BP5 Not assessed Not assessed: no alternate molecular basis of disease was documented for any case carrying this variant.
generic_acmg_combination_rules
BP6 Not met Not met: the ClinVar Benign label is a 0-star laboratory submission, not a 3-star expert-panel assertion.
clinvar generic_acmg_combination_rules
BP7 N/A Not applicable: BP7 requires a synonymous variant; this in-frame duplication alters the encoded protein sequence.
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.