CDC73 c.1066+51C>T, p.?
NM_024529.5:c.1066+51C>T
Variant of Uncertain Significance (VUS)
The intronic CDC73 c.1066+51C>T variant demonstrates no predicted impact on splicing or protein function; it occurs at moderate frequency in population databases and lacks any supporting functional, segregation, de novo, or case-control evidence. Only BP4 is met, and overall evidence is insufficient for a pathogenic or benign classification, resulting in a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
BP4
Genetic Information
Gene & Transcript Details
Gene
CDC73
Transcript
NM_024529.5
MANE Select
Total Exons
17
Strand
Forward (+)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_024529.4 | RefSeq Select | 17 exons | Forward |
| NM_024529.3 | Alternative | 17 exons | Forward |
Variant Details
HGVS Notation
NM_024529.5:c.1066+51C>T
Protein Change
?
Location
Exon 12
(Exon 12 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_024529.5
Genome Browser
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HGVS InputNM_024529:c.1066+51C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.205%
Common
Highest in Population
European (non-Finnish)
0.305%
Common
Global: 0.205%
European (non-Finnish): 0.305%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 195846Alt: 401Homozygotes: 3
ACMG Criteria Applied
None
This variant is present in gnomAD (MAF= 0.205%, 401/195846 alleles, homozygotes = 3) and at a higher frequency in the European (non-Finnish) population (MAF= 0.305%, 245/80254 alleles, homozygotes = 1). The variant frequency does not support application of PM2, BA1, or BS1 criteria.
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: 0.09
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 exon deletion in a LoF gene)". The evidence for this variant shows: c.1066+51C>T is an intronic variant outside canonical splice sites and does not create a null variant. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
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: c.1066+51C>T is noncoding with no amino acid change. Therefore, this criterion is not applied because there is no amino acid change.
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 status. Therefore, this criterion is not applied because de novo status has not been determined.
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 available. Therefore, this criterion is not applied because no functional evidence is present.
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 data for affected individuals. Therefore, this criterion is not applied because prevalence data are unavailable.
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: variant is an intronic variant outside known functional domains. Therefore, this criterion is not applied because it is not located in a mutational hot spot or domain.
PM2
PM2 (Not Applied) Strength Modified
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 with MAF=0.205% and multiple homozygotes. Therefore, this criterion is not applied because the variant is present at moderate frequency in controls.
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 configuration data. Therefore, this criterion is not applied because inheritance in trans is unknown.
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: intronic substitution with no effect on protein length. Therefore, this criterion is not applied because there is no protein length change.
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: noncoding variant with no missense change. Therefore, this criterion is not applied because there is no missense change.
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 data on assumed de novo status. Therefore, this criterion is not applied because de novo status has not been assessed.
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 available. Therefore, this criterion is not applied because segregation has not been evaluated.
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: noncoding variant. Therefore, this criterion is not applied because it is not a missense variant.
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico predictors show no deleterious impact; SpliceAI predicts no splicing effect. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
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 family history provided. Therefore, this criterion is not applied 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: not found in ClinVar or other reputable sources. Therefore, this criterion is not applied because no reputable pathogenic report is available.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0.205%, below >5% threshold. Therefore, this criterion is not applied because allele frequency does not exceed the threshold.
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: MAF=0.205%, which is not greater than expected. Therefore, this criterion is not applied because allele frequency is not unexpectedly high.
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: observed homozygotes in gnomAD but no clinical data. Therefore, this criterion is not applied because health status of individuals 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 available. Therefore, this criterion is not applied 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 information. Therefore, this criterion is not applied because segregation was not assessed.
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: noncoding variant. Therefore, this criterion is not applied because it is not missense.
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 cis/trans data. Therefore, this criterion is not applied because cis/trans status is unknown.
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: single-nucleotide substitution. Therefore, this criterion is not applied because the variant is not an in-frame indel.
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 (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: in silico predictors show no impact; SpliceAI scores of 0 indicate no splicing effect; CADD score 0.09. Therefore, this criterion is applied at Supporting strength because computational evidence consistently indicates no functional 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 such case reported. Therefore, this criterion is not applied because no alternative molecular basis is documented.
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: not reported in ClinVar or other sources. Therefore, this criterion is not applied because no reputable benign report is available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: intronic substitution, not a synonymous coding change. Therefore, this criterion is not applied because the variant is not synonymous.