CUX1 c.2931C>T, p.Phe977=
NM_001202543.1:c.2931C>T
COSMIC ID: COSM1635021, COSM3876699
Variant of Uncertain Significance (VUS)
This is a synonymous (F977=) variant that is extremely rare (PM2 Moderate), with computational evidence indicating no impact on splicing or protein function (BP4 Supporting) and classified as a benign synonymous change (BP7 Supporting). No additional evidence supports pathogenicity or benignity, resulting in a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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.2931C>T
Protein Change
F977=
Location
Exon 18
(Exon 18 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM1635021, COSM3876699
Variant interpretation based on transcript NM_001202543.1
Genome Browser
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HGVS InputNM_001202543:c.2931C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00165%
Rare
Highest in Population
East Asian
0.0109%
Low Frequency
Global: 0.00165%
East Asian: 0.0109%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 242310Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00165%, 4/242310 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0109%, 2/18362 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.43
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 is a known mechanism of disease.' The evidence for this variant shows: it is a synonymous change (c.2931C>T; F977=) and not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce a null effect.
PS1
PS1 (Not Applied) Strength Modified
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 for this variant shows: there is no known pathogenic variant resulting in F977= or equivalent. Therefore, this criterion is not applied at Not Applied strength because no matching pathogenic amino acid change exists.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed).' The evidence for this variant shows: no de novo status has been confirmed. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence is not documented.
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: there are no functional studies available. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been assessed.
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 prevalence data. Therefore, this criterion is not applied at Not Applied strength because there is no statistical enrichment data.
PM1
PM1 (Not Applied) Strength Modified
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: it is a synonymous change outside any described hotspot or functional domain. Therefore, this criterion is not applied at Not Applied strength because it does not reside in a recognized hotspot or domain.
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: it is extremely rare (MAF = 0.00165% in gnomAD). Therefore, this criterion is applied at Moderate strength because it meets the rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
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: no trans observation with a known pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because no trans data exist.
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 synonymous with no protein length change. Therefore, this criterion is not applied at Not Applied strength because there is no length-altering event.
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 pathogenic missense change has been seen.' The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength because it does not alter the amino acid sequence.
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 de novo assumptions. Therefore, this criterion is not applied at Not Applied strength because there is no parental confirmation data.
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 segregation data. Therefore, this criterion is not applied at Not Applied strength because family studies are 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: it is synonymous. Therefore, this criterion is not applied at Not Applied strength because it is not a missense change.
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 (CADD = 0.43, SpliceAI = 0) predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength because in silico evidence is benign.
PP4
PP4 (Not Applied) Strength Modified
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 for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
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 such report exists. Therefore, this criterion is not applied at Not Applied strength because no pathogenic assertions are found.
BA1
BA1 (Not Applied) Strength Modified
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 = 0.00165%, well below the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not excessive.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder.' The evidence for this variant shows: its low frequency is within expected range. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed disease expectation.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age.' The evidence for this variant shows: no healthy adult observation data. Therefore, this criterion is not applied at Not Applied strength because such evidence is missing.
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 assays performed. Therefore, this criterion is not applied at Not Applied strength because no functional data exist.
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 analysis. Therefore, this criterion is not applied at Not Applied strength because family data are unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease.' The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength because it does not meet the missense requirement.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength because no allelic context is documented.
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 synonymous, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because it does not fit the indel context.
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: CADD = 0.43 and SpliceAI scores = 0 predict no impact. Therefore, this criterion is applied at Supporting strength because benign computational evidence is concordant.
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 such case report. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is described.
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: no benign assertion exists. Therefore, this criterion is not applied at Not Applied strength because no reputable benign report is available.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: it is synonymous (F977=) and SpliceAI predicts no splice impact. Therefore, this criterion is applied at Supporting strength because it meets the synonymous no-splice criterion.