Variant classification summary

NM_001202543.1:c.2383C>G

CUX1 · NP_001189472.1:p.(Leu795Val) · NM_001202543.1

GRCh37: chr7:101844927 C>G · GRCh38: chr7:102201647 C>G

Gene: CUX1 Transcript: NM_001202543.1

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting

Variant details

Gene

CUX1

Transcript

NM_001202543.1

Protein

NP_001189472.1:p.(Leu795Val)

gnomAD AF

0.00016734057401535565 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001202543.1:c.2383C>G (p.Leu795Val) in CUX1 is classified as Likely Benign based on ACMG/AMP 2015 criteria.

2

The variant is present in gnomAD v4.1 at low frequency (AF=0.0167%, 270/1,613,476 alleles, 0 homozygotes), meeting PM2_supporting; however, the observation in 270 alleles warrants caution in this assignment.

3

Multiple in silico predictors concordantly support a benign effect: REVEL score 0.067, BayesDel score -0.544, and SpliceAI max delta 0.00 (BP4_supporting).

4

Two independent clinical testing laboratories (Ambry Genetics, CeGaT) have classified this variant as Likely Benign in ClinVar VCV2371264 (BP6_supporting).

5

No case reports, functional studies, or variant-specific literature were identified for this variant. All ClinVar-associated PMIDs are unrelated policy/position statements about newborn screening.

6

With 2 supporting benign criteria (BP4, BP6) versus 1 supporting pathogenic criterion (PM2), the benign evidence outweighs the pathogenic evidence, resulting in a Likely Benign classification per generic ACMG/AMP 2015 combination rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	This is a missense substitution (NM_001202543.1:c.2383C>G; p.Leu795Val) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The PVS1 variant assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No same-amino-acid pathogenic comparator variant identified. No prior reports of a different nucleotide change at c.2383 resulting in the same p.Leu795Val missense change classified as pathogenic.
PS2	N/A	No de novo data available for this variant.
PS3	Not assessed	No variant-specific functional studies identified in the literature or OncoKB. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-level functional evidence. Literature search yielded no in vitro or in vivo functional assays for NM_001202543.1:c.2383C>G (p.Leu795Val).	oncokb
PS4	Not met	No case reports or affected individual observations identified. The variant is present in 270 alleles in gnomAD v4.1 (AF=0.0167%), inconsistent with a rare pathogenic variant. All ClinVar-associated PMIDs are policy/position statements about newborn screening unrelated to CUX1 or this variant.	gnomad_v4 gnomad_v2 clinvar
PS5	Not met	PS5 requires the variant to be classified as pathogenic by a reputable source. ClinVar VCV2371264 is classified as 'Likely benign' by two clinical testing laboratories (Ambry Genetics, CeGaT). No reputable source has classified this variant as pathogenic. ClinVar-associated PMIDs are unrelated newborn screening policy papers that do not mention this variant.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per domain-level analysis. CUX1 does not have an established critical functional domain with defined benign variation tolerance for PM1 application.
PM2	Met	The variant is present at very low frequency in population databases. gnomAD v4.1 reports 270/1,613,476 alleles (AF=0.0167%, 0 homozygotes; grpmax FAF=0.02%). Although not absent, the allele frequency falls below the generic ACMG PM2 threshold of 0.1%. Absent from gnomAD v2.1 and gnomAD-Canada. ClinVar classification of 'Likely benign' from two clinical labs combined with this borderline population frequency warrants human review of PM2 assignment.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics. No established pathogenic comparator variants at the same amino acid residue (Leu795) with a different amino acid change.	pm5_candidates
PM6	N/A	No de novo data available for this variant.
PP1	N/A	No cosegregation data available for this variant.
PP2	N/A	CUX1 lacks established missense constraint metrics (e.g., missense Z-score) and there is no CSPEC/VCEP framework confirming that missense variants are a common mechanism of disease with a low rate of benign missense variation in this gene.
PP3	Not met	Multiple lines of computational evidence support a benign impact. REVEL score is 0.067 (strongly benign-leaning; pathogenic threshold typically >0.5). BayesDel score is -0.544 (benign-leaning; pathogenic threshold typically >0.1). SpliceAI predicts no splicing impact (max delta score = 0.00). These in silico predictions collectively argue against a deleterious effect.	revel bayesdel spliceai
PP4	N/A	No specific phenotype or clinical data available for the individuals carrying this variant.
PP5	Not met	PP5 requires the variant to be classified as pathogenic by a reputable source. ClinVar VCV2371264 is classified as 'Likely benign' (not pathogenic) by two clinical laboratories. All ClinVar-associated PMIDs are unrelated policy/position statements about newborn screening that do not mention CUX1 or variant c.2383C>G.	clinvar
BA1	Not met	The variant allele frequency (gnomAD v4.1 AF=0.0167%, grpmax FAF=0.02%) is well below the BA1 threshold of 1% for generic ACMG application.	gnomad_v4
BS1	Not met	The variant allele frequency (gnomAD v4.1 AF=0.0167%, grpmax FAF=0.02%) is below the BS1 threshold of 0.3% for generic ACMG application.	gnomad_v4
BS2	N/A	No homozygotes observed in gnomAD, and no data on observation of the variant in healthy adults for a fully penetrant dominant disorder.
BS3	Not assessed	No variant-specific functional studies identified that demonstrate no deleterious effect. OncoKB reports no variant-level evidence. Literature search did not identify in vitro or in vivo functional assays for this variant.	oncokb
BS4	N/A	No cosegregation data showing non-segregation with disease available.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. For CUX1, germline disease association is supported only by literature without an official CSPEC/VCEP framework, and there is insufficient evidence that truncating variants are the primary (rather than one of several) mechanism of disease.	pvs1_gene_context
BP2	N/A	Not observed in trans with a known pathogenic variant. No data on co-occurrence with pathogenic variants in the same gene.
BP4	Met	Multiple lines of computational evidence support a benign impact. REVEL score is 0.067 (strongly predictive of benign; pathogenic threshold >0.5). BayesDel score is -0.544 (predictive of benign; pathogenic threshold >0.1). SpliceAI predicts no splicing impact (max delta score = 0.00). Concordant benign predictions across three independent in silico tools.	revel bayesdel spliceai
BP5	N/A	No alternative molecular basis for disease observed in a case harboring this variant.
BP6	Met	Two reputable clinical testing laboratories (Ambry Genetics and CeGaT Center for Human Genetics Tuebingen) have independently classified this variant as 'Likely benign' in ClinVar (VCV2371264). Both submissions are criteria-provided, clinical testing tier. This satisfies the BP6 requirement that a reputable source reports the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants. NM_001202543.1:c.2383C>G is a missense variant (p.Leu795Val), not synonymous.

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.