Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001127208.3 | MANE Select | 9589 nt | 297–6305 |
| NM_001127208.1 | Alternative | 9677 nt | 387–6395 |
| NM_001127208.2 | RefSeq Select | 9796 nt | 488–6496 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TET2 R1516* variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein, leading to predicted gene inactivation. Functional evidence indicates that such truncating mutations abrogate TET2's enzymatic function to generate 5-hydroxymethylcytosine, supporting a damaging effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.16 | -8 bp |
| Donor Loss (DL) | 0.03 | 270 bp |
| Acceptor Gain (AG) | 0.34 | 10 bp |
| Donor Gain (DG) | 0.0 | 10 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "PVS1 – 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: NM_001127208.2:c.4546C>T introduces a premature stop codon (R1516*), resulting in a null allele. Therefore, this criterion is applied at Very Strong strength because this truncating mutation occurs in a gene where LoF is a known disease mechanism.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no previously reported pathogenic variant resulting in the same R1516 amino acid change. Therefore, this criterion is not applied at Not Applied because the variant does not match a known pathogenic amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo segregation data are available. Therefore, this criterion is not applied at Not Applied due to lack of de novo confirmation.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: in vitro studies demonstrate that the R1516* truncation abolishes the C-terminal catalytic domain of TET2, eliminating its enzymatic activity to generate 5-hydroxymethylcytosine. Therefore, this criterion is applied at Strong strength because functional assays confirm a damaging effect.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied at Not Applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "PM1 – Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: R1516* is not located within a designated mutational hotspot beyond the fact that it truncates the protein, and there is no specific domain hotspot annotation. Therefore, this criterion is not applied at Not Applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: a minor allele frequency of 0.00152% in gnomAD, which is below the 0.1% threshold. 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: "PM3 – Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no information on trans configuration with another pathogenic variant, and TET2-associated disease is not strictly recessive. Therefore, this criterion is not applied at Not Applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: R1516* is a nonsense variant creating a truncation rather than an in-frame change. Therefore, this criterion is not applied at Not Applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: R1516* is a nonsense variant, not a missense change. Therefore, this criterion is not applied at Not Applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "PM6 – Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no segregation or de novo data available. Therefore, this criterion is not applied at Not Applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "PP1 – Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "PP2 – 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: R1516* is a nonsense variant, not a missense change. Therefore, this criterion is not applied at Not Applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "PP3 – 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 tools yield a CADD score of 7.96 (benign range) and SpliceAI scores below thresholds for significant splicing impact. Therefore, this criterion is not applied at Not Applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – 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 information provided. Therefore, this criterion is not applied at Not Applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "PP5 – Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: the variant is not reported in ClinVar or other reputable databases. Therefore, this criterion is not applied at Not Applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF of 0.00152%, below any BA1 threshold. Therefore, this criterion is not applied at Not Applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "BS1 – Allele frequency is greater than expected for the disorder". The evidence for this variant shows: frequency is below expected thresholds. Therefore, this criterion is not applied at Not Applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no data on healthy individuals carrying this variant. Therefore, this criterion is not applied at Not Applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "BS3 – Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied at Not Applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "BS4 – 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.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "BP1 – Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: R1516* is a nonsense variant, not missense. Therefore, this criterion is not applied at Not Applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – 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 observations. Therefore, this criterion is not applied at Not Applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "BP3 – In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: R1516* is a nonsense variant. Therefore, this criterion is not applied at Not Applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: mixed computational predictions with no strong support for benign. Therefore, this criterion is not applied at Not Applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "BP5 – Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied at Not Applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "BP6 – Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied at Not Applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "BP7 – Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: this is a nonsense variant, not synonymous. Therefore, this criterion is not applied at Not Applied.