Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001145661.2 | Alternative | 3470 nt | 436–1878 |
| NM_001145661.1 | Alternative | 3484 nt | 436–1878 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
BS1, BP4, BP7
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratories) and as Benign (1 clinical laboratories)."
COSMIC Somatic Evidence
OpenFunctional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 24 bp |
| Donor Loss (DL) | 0.0 | 428 bp |
| Acceptor Gain (AG) | 0.0 | 264 bp |
| Donor Gain (DG) | 0.0 | 400 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'; the evidence for this variant shows it is synonymous and does not introduce a null allele; 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 known pathogenic variant regardless of nucleotide change'; the evidence for this variant shows 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'; no de novo data are available for this variant; therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect'; there are no functional study data 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'; no case-control or affected individual frequency data are available; 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 or well-established functional domain without benign variation'; this variant is not located in a known hotspot or critical 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 shows a MAF of 0.0264% in gnomAD (well below thresholds for common variation); therefore, PM2 is applied at Moderate strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'; there are no data on occurrence in trans with another variant for this gene; 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'; this variant is synonymous and does not alter 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'; this variant is synonymous with no amino acid change; 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'; there is no assumed de novo occurrence data; 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'; segregation data are not 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'; this 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'; computational tools (CADD -0.08, SpliceAI 0) predict no impact; therefore, PP3 is not applied.
PP4 (Not Applied)
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'; clinical phenotype and family history data are not 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 without accessible evidence'; no reputable source classifies this variant as pathogenic; therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is greater than 5% in population databases'; the observed frequency (0.0264%) is well below this threshold; therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'; 0.0264% frequency is below expected maximum for GATA2‐related conditions; therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age'; no data demonstrate observation in unaffected individuals; therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect'; no functional study data are available; therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'; segregation analysis data are not available; therefore, BS4 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'; this variant is synonymous; therefore, BP1 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 phasing data are available; therefore, BP2 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'; this variant is synonymous; therefore, BP3 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'; CADD score of -0.08 and SpliceAI scores of zero indicate no predicted impact; therefore, BP4 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 reports exist; therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence'; although ClinVar lists benign submissions, detailed evidence is not accessible and internal policy restricts application of BP6 in absence of primary data; therefore, BP6 is not applied.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'; this variant is synonymous and SpliceAI predicts no splicing impact; therefore, BP7 is applied at Supporting strength.