Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_181500.2 | Alternative | 3033 nt | 128–2158 |
| NM_181500.3 | Alternative | 3033 nt | 128–2158 |
| NM_181500.4 | Alternative | 2923 nt | 25–2055 |
| NM_181500.1 | Alternative | 2925 nt | 9–2039 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -169 bp |
| Donor Loss (DL) | 0.01 | 2 bp |
| Acceptor Gain (AG) | 0.0 | -76 bp |
| Donor Gain (DG) | 0.96 | -2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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.' The evidence for this variant shows: 'c.1756C>T (p.R586W) is a missense change, not predicted to result in loss of function.' Therefore, this criterion is not applied because the variant is not a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: 'No previously established pathogenic variant at amino acid residue R586 in CUX1.' Therefore, this criterion is not applied because there is no known pathogenic variant with the same amino acid change.
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 for this variant shows: 'No data on de novo occurrence or parental testing.' Therefore, this criterion is not applied because de novo status is not confirmed.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: 'No functional studies have been performed for CUX1 p.R586W.' Therefore, this criterion is not applied because functional evidence is lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: 'No case-control or cohort data reporting enrichment in affected individuals.' Therefore, this criterion is not applied because there is no statistical evidence of increased prevalence.
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 for this variant shows: 'Residue R586 is not located in a recognized mutational hotspot or critical functional domain of CUX1.' Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: 'Present in gnomAD at MAF = 0.00485%, which is extremely low (<0.1%).' Therefore, this criterion is applied at Moderate strength because the variant is observed at an extremely low frequency in population databases.
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 for this variant shows: 'CUX1-associated disease is haploinsufficiency (dominant), and there is no evidence of a second pathogenic allele in trans.' Therefore, this criterion is not applied.
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 for this variant shows: 'This is a missense variant without change in protein length.' Therefore, this criterion is not applied.
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 for this variant shows: 'No different pathogenic missense change has been reported at residue R586.' Therefore, this criterion is not applied.
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 for this variant shows: 'No information on any de novo occurrence.' Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: 'No family segregation data available.' Therefore, this criterion is not applied.
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 for this variant shows: 'CUX1 disease mechanism is haploinsufficiency via loss of function, and missense variants are not established as a common mechanism.' Therefore, this criterion is not applied.
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: 'SpliceAI predicts a high impact on splicing (score = 0.96), indicating potential alteration of normal splicing.' Therefore, this criterion is applied at Supporting strength because in silico tools predict a deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: 'No patient phenotype or family history information was provided.' Therefore, this criterion is not applied.
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 for this variant shows: 'ClinVar lists it as Uncertain Significance; no reputable pathogenic assertion exists.' Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: 'MAF = 0.00485%, which is well below any high-frequency threshold.' Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: 'MAF = 0.00485%, which is below thresholds for exclusion of pathogenicity.' Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age.' The evidence for this variant shows: 'Present in gnomAD but CUX1-associated conditions may have variable penetrance; no direct evidence of benign carriers with confirmed health status.' Therefore, this criterion is not applied.
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 for this variant shows: 'No functional studies demonstrating benign impact.' Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: 'No family data to assess segregation.' Therefore, this criterion is not applied.
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease.' The evidence for this variant shows: 'CUX1 disease mechanism involves haploinsufficiency due to loss of function; p.R586W is a missense change.' Therefore, this criterion is applied at Supporting strength because the variant type is inconsistent with the known mechanism.
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 for this variant shows: 'No data on phase with another pathogenic variant.' Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: 'This is a single nucleotide missense change, not an in-frame indel in a repetitive region.' Therefore, this criterion is not applied.
BP4 (Not Applied)
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 for this variant shows: 'Computational evidence (SpliceAI) predicts a deleterious impact on splicing.' Therefore, this criterion is not applied.
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 for this variant shows: 'No case reports with an alternative molecular diagnosis.' Therefore, this criterion is not applied.
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 for this variant shows: 'No reputable benign assertion exists.' Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing and no change to the amino acid.' The evidence for this variant shows: 'This is a missense variant, not synonymous.' Therefore, this criterion is not applied.