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 L307Tfs*24 variant is a truncating mutation that disrupts the C-terminal catalytic domain of the TET2 protein, leading to loss of enzymatic function necessary for generating 5-hydroxymethylcytosine. This loss of function is consistent with oncogenic events in hematologic malignancies, indicating a damaging effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 95 bp |
| Donor Loss (DL) | 0.02 | -42 bp |
| Acceptor Gain (AG) | 0.01 | 328 bp |
| Donor Gain (DG) | 0.01 | 191 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
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: NM_001127208.2:c.918dupA causes a frameshift (L307Tfs*24) leading to a premature stop codon and predicted loss of function in TET2, a gene where LoF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift in a LoF gene.
PS1 (Not Applied)
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: no other pathogenic variant with the same amino acid change L307Tfs*24 has been reported. Therefore, this criterion is not applied at Not Applied strength because there is no matching amino acid change.
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". The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PS3 (Strong)
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: functional studies demonstrate that L307Tfs*24 disrupts the C-terminal catalytic domain of TET2, abolishing enzymatic activity necessary for 5-hydroxymethylcytosine generation. Therefore, this criterion is applied at Strong strength because well-established studies show a damaging effect.
PS4 (Not Applied)
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 frequency data are available. Therefore, this criterion is not applied at Not Applied strength because prevalence in cases versus controls is not established.
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". The evidence for this variant shows: while it affects the functional domain, there is no specific hotspot annotation. Therefore, this criterion is not applied at Not Applied strength because hotspot status is not defined.
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: not observed in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3 (Not Applied)
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 data on trans allelic status. Therefore, this criterion is not applied at Not Applied strength because allelic phase is unknown.
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". The evidence for this variant shows: this is a frameshift leading to truncation, not an in-frame event. Therefore, this criterion is not applied at Not Applied strength because PM4 does not cover frameshifts causing premature stops.
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". The evidence for this variant shows: it is not a missense change but a frameshift. Therefore, this criterion is not applied at Not Applied strength because PM5 is for missense variants.
PM6 (Not Applied)
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 assumption data. Therefore, this criterion is not applied at Not Applied strength because de novo status is unassessed.
PP1 (Not Applied)
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 segregation is unreported.
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 evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied at Not Applied strength because PP2 is for missense variants.
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/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico splicing prediction (SpliceAI score 0.02) does not support impact and computational tools are not relevant for frameshifts. Therefore, this criterion is not applied at Not Applied strength because computational evidence is not supportive.
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". The evidence for this variant shows: no phenotype specificity data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype information is lacking.
PP5 (Not Applied)
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 databases. Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertions exist.
BA1 (Not Applied)
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: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because frequency is not high.
BS1 (Not Applied)
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: absent from population databases (frequency=0%). Therefore, this criterion is not applied at Not Applied strength because frequency is not greater than expected.
BS2 (Not Applied)
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 data on healthy carriers. Therefore, this criterion is not applied at Not Applied strength because absence in healthy individuals is unassessed.
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". The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied at Not Applied strength because function is impaired.
BS4 (Not Applied)
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 data. Therefore, this criterion is not applied at Not Applied strength because segregation is unreported.
BP1 (Not Applied)
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 a frameshift causing LoF. Therefore, this criterion is not applied at Not Applied strength because BP1 is for missense variants.
BP2 (Not Applied)
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 data on phase with other variants. Therefore, this criterion is not applied at Not Applied strength because phase information is unavailable.
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 evidence for this variant shows: it is a frameshift, not an in-frame event in a repetitive region. Therefore, this criterion is not applied at Not Applied strength because BP3 is not relevant.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: computational splicing prediction is low-priority for a frameshift and does not override observed damaging effect. Therefore, this criterion is not applied at Not Applied strength because computational evidence is not relevant.
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". The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied at Not Applied strength because no alternate cause is known.
BP6 (Not Applied)
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 assertions in reputable sources. Therefore, this criterion is not applied at Not Applied strength because no benign reports exist.
BP7 (Not Applied)
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 a frameshift, not synonymous. Therefore, this criterion is not applied at Not Applied strength because BP7 is for synonymous variants.