CUX1 c.4214G>A, p.Gly1405Asp
NM_001202543.1:c.4214G>A
COSMIC ID: COSM6384751, COSM9990004
Variant of Uncertain Significance (VUS)
This variant is classified as a VUS because it meets PM2 (Moderate) for rarity but also meets BP4 (Supporting) for benign computational evidence, with no additional pathogenic or benign criteria to allow definitive classification.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
CUX1
Transcript
NM_001202543.1
Total Exons
24
Strand
Forward (+)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001202543.2 | Alternative | 24 exons | Forward |
Variant Details
HGVS Notation
NM_001202543.1:c.4214G>A
Protein Change
G1405D
Location
Exon 24
(Exon 24 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1405 in gene CUX1
Alternate Identifiers
COSM6384751, COSM9990004
Variant interpretation based on transcript NM_001202543.1
Genome Browser
Loading genome browser...
HGVS InputNM_001202543:c.4214G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.018%
Low Frequency
Highest in Population
European (non-Finnish)
0.0295%
Low Frequency
Global: 0.018%
European (non-Finnish): 0.0295%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 33272Alt: 6Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.018%, 6/33272 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0295%, 5/16970 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1405 in gene CUX1
Functional Summary
The CUX1 G1405D variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.084
0.084
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
primateai: D
Benign:
CADD: 2.14polyphen_prediction: benignmetasvm: Tmetalr: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (G1405D), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
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: there is no previously established pathogenic variant causing G1405D. Therefore, this criterion is not applied at Not Applied strength because no known pathogenic amino acid change at this position exists.
PS2
PS2 (Not Applied) Strength Modified
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 confirmation. Therefore, this criterion is not applied at Not Applied strength because de novo status is not established.
PS3
PS3 (Not Applied) Strength Modified
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. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assessed experimentally.
PS4
PS4 (Not Applied) Strength Modified
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 studies demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because no case prevalence data are available.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation". The evidence for this variant shows: G1405D is not reported in a known hotspot or critical domain. Therefore, this criterion is not applied at Not Applied strength because no hotspot or domain evidence is present.
PM2
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: MAF = 0.018% in gnomAD (6/33272 alleles), extremely rare (<0.1%). Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because trans data are unavailable.
PM4
PM4 (Not Applied) Strength Modified
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: it is a missense substitution without length change. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic". The evidence for this variant shows: no other pathogenic missense at residue 1405. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variant at the same residue is known.
PM6
PM6 (Not Applied) Strength Modified
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 assumed de novo status. Therefore, this criterion is not applied at Not Applied strength because de novo status without confirmation is not reported.
PP1
PP1 (Not Applied) Strength Modified
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. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is lacking.
PP2
PP2 (Not Applied) Strength Modified
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: insufficient data on background missense rate or disease mechanism in CUX1. Therefore, this criterion is not applied at Not Applied strength because gene-specific missense constraint is unestablished.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational tools (REVEL 0.08, CADD, PolyPhen-2, MetaSVM, MetaLR) predict benign impact and SpliceAI shows no splicing effect. Therefore, this criterion is not applied at Not Applied strength because in silico evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
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 information provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity data are absent.
PP5
PP5 (Not Applied) Strength Modified
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: no reputable source classifies this as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no such report exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases". The evidence for this variant shows: MAF = 0.018%, well below 5%. Therefore, this criterion is not applied at Not Applied strength because frequency is not high enough.
BS1
BS1 (Not Applied) Strength Modified
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 = 0.018%, not exceeding expected threshold. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed disease-specific expectation.
BS2
BS2 (Not Applied) Strength Modified
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: presence in gnomAD but no phenotype data for carriers. Therefore, this criterion is not applied at Not Applied strength because carrier health status is unknown.
BS3
BS3 (Not Applied) Strength Modified
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 performed. Therefore, this criterion is not applied at Not Applied strength because functional assay data are not available.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because family studies are lacking.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which only loss of function causes disease". The evidence for this variant shows: mechanism of CUX1-associated disease is not definitively loss-of-function only. Therefore, this criterion is not applied at Not Applied strength because gene-specific mechanism is unclear.
BP2
BP2 (Not Applied) Strength Modified
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 cis/trans configuration with pathogenic variants. Therefore, this criterion is not applied at Not Applied strength because phase information is unavailable.
BP3
BP3 (Not Applied) Strength Modified
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: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because variant type does not match.
BP4
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 for this variant shows: REVEL score 0.08 (<0.15), benign predictions from CADD, PolyPhen-2, MetaSVM, MetaLR, and no splicing impact by SpliceAI. Therefore, this criterion is applied at Supporting strength because in silico analyses consistently predict a benign impact.
BP5
BP5 (Not Applied) Strength Modified
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 cases reported with an alternate molecular diagnosis. Therefore, this criterion is not applied at Not Applied strength because no such clinical context is provided.
BP6
BP6 (Not Applied) Strength Modified
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: ClinVar reports one likely benign but with accessible evidence. Therefore, this criterion is not applied at Not Applied strength because the source evidence is accessible.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and no change to amino acid". The evidence for this variant shows: it is missense, not synonymous. Therefore, this criterion is not applied at Not Applied strength because variant is not synonymous.