About CUX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CUX1 c.2383C>G, p.(Leu795Val)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
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.
BP6Supporting
BP6 · supporting
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.
Recorded classification: Likely benign
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.
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
270 / 1,613,476 alleles
gnomAD v4.1: 270 / 1,613,476 alleles. Recorded AF 0.000167341. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006516780710329097, 12/18414 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Likely benign.
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 7 not met · 3 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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).
Two independent clinical testing laboratories (Ambry Genetics, CeGaT) have classified this variant as Likely Benign in ClinVar VCV2371264 (BP6_supporting).
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).
No criteria match.
Met · 3
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.0167% (270/1
- 613
- 476 alleles
- 0 homozygotes)
- grpmax FAF=0.02%
Still missing
- 270 alleles in gnomAD v4.1 is borderline for PM2
- variant is not truly absent
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
BP6 SupportingTwo 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. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2371264: Likely benign from Ambry Genetics (SCV003712369) and CeGaT (SCV005433495)
Sources
Not met · 7 · evaluated, threshold not reached
PS4 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. Details ▾Hide ▴
Evidence considered
- No affected cases identified
- 270 alleles in gnomAD v4.1
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Variant not in a statistically significant hotspot
- no established PM1 domain for CUX1
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.067 (benign)
- BayesDel=-0.544 (benign)
- SpliceAI max delta=0.0 (no splice impact)
Sources
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification is 'Likely benign'
- no reputable source classifies as pathogenic
Sources
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. Details ▾Hide ▴
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. Details ▾Hide ▴
PS5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification is 'Likely benign'
- not pathogenic
- 2 clinical lab submissions
Sources
Not assessed · 3 · no assessment recorded
PS1 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. Details ▾Hide ▴
Still missing
- No known pathogenic variant at the same amino acid residue (Leu795) for comparison
PS3 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). Details ▾Hide ▴
Evidence considered
- OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence
Still missing
- No functional studies available for this variant
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional evidence found
Still missing
- No functional studies available
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Missense variant p.Leu795Val
- not a null variant
Sources
PS2 N/ANo de novo data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable 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. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator variants identified
Sources
pm5_candidates
PM6 N/ANo de novo data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo cosegregation data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP2 N/ACUX1 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. Details ▾Hide ▴
Still missing
- No gene-level missense constraint data for PP2 assessment
PP4 N/ANo specific phenotype or clinical data available for the individuals carrying this variant. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo homozygotes observed in gnomAD, and no data on observation of the variant in healthy adults for a fully penetrant dominant disorder. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo cosegregation data showing non-segregation with disease available. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
- CUX1 germline disease context is literature-only
- no CSPEC/VCEP to establish primary truncating mechanism
Sources
pvs1_gene_context
BP2 N/ANot observed in trans with a known pathogenic variant. No data on co-occurrence with pathogenic variants in the same gene. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo alternative molecular basis for disease observed in a case harboring this variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants. NM_001202543.1:c.2383C>G is a missense variant (p.Leu795Val), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants
Identifiers
- Gene
- CUX1
- Transcript
- NM_001202543.1
- Coding (HGVS c.)
- NM_001202543.1:c.2383C>G
- Protein (HGVS p.)
- NP_001189472.1:p.(Leu795Val)
- GRCh38
- chr7:102201647 C>G
- GRCh37
- chr7:101844927 C>G
- ClinVar
- 2371264
Gene diagram
Every interpreted variant in CUX1, mapped onto the exon structure of NM_001202543.1. Select a row to find it on the plot.
CUX1NM_001202543.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CUX1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
270 / 1,613,476 alleles
AF 0.000167 · 0 homozygotes · FAF 0.0002
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00017 · 270 / 1,613,476 alleles · 0 hom · FAF 0.0002
| European (non-Finnish)263 / 1,179,904 | 0.00022 |
| Admixed American3 / 60,010 | 5e-05 |
| Remaining individuals3 / 62,460 | 4.8e-05 |
| African/African American1 / 74,916 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006516780710329097, 12/18414 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.067
- BayesDel
- -0.544
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.067 (benign)
- BayesDel=-0.544 (benign)
- SpliceAI max delta=0.0 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous variants. NM_001202543.1:c.2383C>G is a missense variant (p.Leu795Val), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.067. BayesDel score = -0.54419.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015Position statement by the European Society of Human Genetics on the continued importance of targeted approaches in newborn screening programmes. Discusses ethical and practical considerations of whole-genome sequencing in newborn screening. NM_001202543.1:c.2383C>G was not identified in this paper.Does not name this variant
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PMID 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.Edwards JG et al. · 2015Joint statement by ACMG, ACOG, NSGC, Perinatal Quality Foundation, and SMFM on considerations for expanded carrier screening in reproductive medicine. NM_001202543.1:c.2383C>G was not identified in the abstract or title.Does not name this variant
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PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014Workshop report on the appropriateness of newborn screening for alpha-1 antitrypsin (AAT) deficiency. Discusses clinical features and screening rationale for AAT deficiency. NM_001202543.1:c.2383C>G was not identified in this paper.Does not name this variant
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PMID 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.Therrell BL et al. · 2013Recommendations from the Secretary of HHS Advisory Committee on Heritable Disorders in Newborns and Children regarding inclusion of newborn screening bloodspot collection device serial numbers on birth certificates. NM_001202543.1:c.2383C>G was not identified in the abstract or title.Does not name this variant
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Guidelines from the Newborn Screening Translational Research Network (NBSTRN) on parental permission for pilot newborn screening research. NM_001202543.1:c.2383C>G was not identified in the abstract or title.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
270 / 1,613,476 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2371264/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-101844927-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-102201647-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-102201647-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001202543.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/CUX1/L795V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CUX1+c.2383C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
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= 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006516780710329097, 12/18414 alleles, homozygotes = 0).
ClinVar
Error retrieving ClinVar entry.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.