NM_001202543.1:c.2383C>G (p.Leu795Val) in CUX1 is classified as Likely Benign based on ACMG/AMP 2015 criteria. 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.1 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).2 Two independent clinical testing laboratories (Ambry Genetics, CeGaT) have classified this variant as Likely Benign in ClinVar VCV2371264 (BP6_supporting).3 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. 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).4
CUX1
Final classification
Likely Benign
CUX1 c.2383C>G · p.Leu795Val
CUX1
NM_001202543.1:c.2383C>G (p.Leu795Val) in CUX1 is classified as Likely Benign based on ACMG/AMP 2015 criteria.
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, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6
Likely Benign
CUX1 c.2383C>G
PM2 + BP4 + BP6
→
Likely Benign
Gene diagram
· NM_001202543.1 · variants mapped to exon structure
CUX1
NM_001202543.1
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 9 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
review
Pathogenic
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 v4.1 AF=0.0167% (270/1613476 alleles
✓
BP4
supporting
Benign
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=0.067BayesDel=-0.544SpliceAI max delta=0.0
✓
BP6
supporting
Benign
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 VCV2371264: Likely benign from Ambry Genetics (SCV003712369) and CeGaT (SCV005433495)
Assessed · not applied
Pathogenic
PS1
No same-amino-acid pathogenic comparator variant identified.
PS3
No variant-specific functional studies identified in the literature or OncoKB.
PS4
No case reports or affected individual observations identified.
PM1
This variant does not lie in a statistically significant mutational hotspot per domain-level analysis.
PP3
Multiple lines of computational evidence support a benign impact.
PP5
PP5 requires the variant to be classified as pathogenic by a reputable source.
Benign
BA1
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.
BS1
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.
BS3
No variant-specific functional studies identified that demonstrate no deleterious effect.
N/A · 13
PVS1 · PS2 · PM5 · PM6 · PP1 · PP2 · PP4 · BS2 · BS4 · BP1 · BP2 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000167341; MAF= 0.01673%, 270/1613476 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000222899; MAF= 0.02229%, 263/1179904 alleles, homozygotes = 0); grpmax FAF= 0.0002003.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006516780710329097, 12/18414 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.017%
· 270 / 1,613,476
0 hom · FAF 0.02%
0 hom · FAF 0.02%
European (non-Finnish) 263 / 1,179,904 |
0.022% |
Admixed American 3 / 60,010 |
0.005% |
Remaining individuals 3 / 62,460 |
0.0048% |
African/African American 1 / 74,916 |
0.0013% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
0.065%
· 12 / 18,414
0 hom · FAF 0.059%
0 hom · FAF 0.059%
European (non-Finnish) 12 / 11,736 |
0.1% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.067. BayesDel score = -0.54419.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CUX1, a transcription factor, is frequently altered in several cancers types by deletion, mutation or translocation.
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.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR