Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and 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) | 0.01 | 70 bp |
| Donor Loss (DL) | 0.01 | -140 bp |
| Acceptor Gain (AG) | 0.0 | 358 bp |
| Donor Gain (DG) | 0.0 | 233 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 (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 it is a synonymous change (A724=) with no predicted impact on splicing or the gene product. Therefore, this criterion is not applied.
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 it is synonymous (no amino acid change). Therefore, this criterion is not applied.
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." There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied.
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." There are no functional studies available for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." There are no case–control or patient prevalence data for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
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 A724= position is not known to reside in a POLE mutational hotspot or key functional domain. 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 a MAF of 0.004% in gnomAD. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." There is no data on allelic phase with another variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions or stop-loss variants." This is a synonymous variant with no protein length change. 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." This variant is synonymous, not missense. 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." No de novo data are available. 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." No segregation data are 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 variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
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." Computational evidence for this variant suggests a benign impact (CADD 0.75, SpliceAI 0.01). Therefore, this criterion is not applied.
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." No phenotype-specific data are available. 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." ClinVar reports this variant as likely benign or VUS, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The variant frequency is 0.004%, well below 5%. 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 observed allele frequency does not exceed expected thresholds for a dominant or recessive POLE-associated disorder. 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 fully penetrant dominant disorder." There are no specific reports of this variant in healthy adults with confirmed clinical follow-up. 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." No functional studies have been performed. 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." No segregation data are available. Therefore, this criterion is not applied.
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 variant is synonymous. Therefore, this criterion is not applied.
BP2 (Not Applied)
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." No such phase data are available. 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 variant is synonymous. Therefore, this criterion is not applied.
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 a CADD score of 0.75 and SpliceAI of 0.01, indicating no functional impact. Therefore, this criterion is applied at Supporting strength.
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." No such case data are available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." ClinVar includes five laboratory submissions reporting this variant as likely benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and no conservation." The variant is synonymous (A724=) and SpliceAI predicts no splice impact. Therefore, this criterion is applied at Supporting strength.