Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001202543.1 | Alternative | 13882 nt | 128–4678 |
| NM_001202543.2 | Alternative | 13766 nt | 25–4575 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The CUX1 T218Nfs*7 variant is a truncating mutation in the CUX1 gene, which functions as a haploinsufficient tumor suppressor. Functional evidence indicates that truncating mutations in CUX1 lead to reduced protein expression, activation of the PI3K signaling pathway, and tumor growth. This variant is therefore likely to have a damaging effect.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -5 bp |
| Donor Loss (DL) | 0.0 | 227 bp |
| Acceptor Gain (AG) | 0.01 | -27 bp |
| Donor Gain (DG) | 0.0 | 61 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence shows: NM_001202543.1:c.652dupA is a frameshift variant predicted to introduce a premature stop codon (T218Nfs*7) not in the last exon, likely leading to nonsense-mediated decay. Therefore, PVS1 is applied at Very Strong strength because the variant is a null variant in a gene where loss of function is the established disease mechanism.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence shows: no known pathogenic variant causes the same amino acid change T218Nfs*7 by a different nucleotide change. Therefore, PS1 is not applied because the criterion is not met.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence shows: de novo status has not been assessed; parental testing data are unavailable. Therefore, PS2 is not applied because evidence of a confirmed de novo occurrence is not available.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence shows: functional studies demonstrate that CUX1 truncating mutations reduce protein expression, activate the PI3K signaling pathway, and promote tumor growth. Therefore, PS3 is applied at Strong strength because well-established functional data support a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls'. The evidence shows: there are no case-control or cohort data for NM_001202543.1:c.652dupA. Therefore, PS4 is not applied because prevalence data in affected individuals are lacking.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence shows: this variant is a frameshift and is not located in a defined mutational hotspot or known functional domain. Therefore, PM1 is not applied because it does not meet hotspot/domain criteria.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence shows: NM_001202543.1:c.652dupA is not present in population databases including gnomAD. Therefore, PM2 is applied at Moderate strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence shows: CUX1-related disease is autosomal dominant due to haploinsufficiency, and trans data are not relevant. Therefore, PM3 is not applied because the inheritance and data do not support this criterion.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence shows: the variant causes a frameshift with premature truncation, not an in-frame change. Therefore, PM4 is not applied because it is not an in-frame indel or stop-loss.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence shows: this is a frameshift variant, not missense, and no missense variants at this residue are reported. Therefore, PM5 is not applied because the variant is not missense.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows: no data on de novo occurrence without parental confirmation. Therefore, PM6 is not applied because there is no evidence of an assumed de novo event.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence shows: no family segregation data are available. Therefore, PP1 is not applied because segregation information is lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence shows: the variant is a frameshift, not missense. Therefore, PP2 is not applied because it is not applicable to this variant type.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect'. The evidence shows: in silico tools including SpliceAI predict minimal impact on splicing (score 0.01) and no deleterious effect. Therefore, PP3 is not applied because computational evidence does not support a damaging impact.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence shows: no phenotype or clinical data are provided. Therefore, PP4 is not applied because phenotype specificity data are lacking.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence shows: the variant is not reported in ClinVar or other reputable sources. Therefore, PP5 is not applied because no such reports exist.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence shows: the variant is absent from population databases. Therefore, BA1 is not applied because allele frequency is not above the high-frequency threshold.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence shows: the variant is absent from controls. Therefore, BS1 is not applied because allele frequency is not greater than expected.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence shows: no observations in healthy individuals are documented. Therefore, BS2 is not applied because such data are absent.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence shows: functional studies demonstrate damaging effects of truncating CUX1 variants. Therefore, BS3 is not applied because functional data indicate a damaging effect.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence shows: no segregation data are available. Therefore, BS4 is not applied because segregation information is lacking.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. The evidence shows: this is a loss-of-function frameshift variant, not missense. Therefore, BP1 is not applied because it does not apply to this variant type.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence shows: no data on trans or cis observations with another variant. Therefore, BP2 is not applied because such observations are not documented.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in repetitive region without known function'. The evidence shows: this is a frameshift resulting in truncation, not an in-frame indel. Therefore, BP3 is not applied because it does not meet the criterion.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence shows: SpliceAI predicts minimal impact on splicing (score 0.01) and no deleterious computational predictions. Therefore, BP4 is applied at Supporting strength because computational evidence suggests no splicing impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence shows: no case reports describe an alternate molecular basis. Therefore, BP5 is not applied because no such cases exist.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence shows: the variant is not reported in any reputable database as benign. Therefore, BP6 is not applied because no such reports are available.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence shows: this is a frameshift variant, not synonymous. Therefore, BP7 is not applied because it does not meet the criterion.