Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004972.4 | MANE Select | 7023 nt | 468–3866 |
| NM_004972.2 | Alternative | 5097 nt | 495–3893 |
| NM_004972.3 | RefSeq Select | 5285 nt | 495–3893 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The JAK2 H538_K539delinsL variant has been functionally characterized as activating. Expression of this mutation in immortalized mouse progenitor B cells demonstrated increased protein and downstream pathway activation, as well as cytokine-independent growth, indicating a gain-of-function effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -31 bp |
| Donor Loss (DL) | 0.0 | 28 bp |
| Acceptor Gain (AG) | 0.0 | -99 bp |
| Donor Gain (DG) | 0.0 | -8 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: H538_K539delinsL is an in-frame deletion/insertion altering amino acids but does not introduce a premature stop codon or disrupt canonical splice sites. Therefore, this criterion is not applied at Not Applied because the variant is not a null LoF variant.
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 variant producing H538_K539delinsL has been reported as pathogenic. Therefore, this criterion is not applied at Not Applied because there is no known identical amino acid change in a different nucleotide context.
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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied at Not Applied due to lack of de novo data.
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: functional characterization demonstrated that H538_K539delinsL is activating, with increased downstream pathway activation and cytokine-independent growth in mouse progenitor B cells. Therefore, this criterion is applied at Strong strength because robust functional studies support a damaging gain-of-function 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 or prevalence data. Therefore, this criterion is not applied at Not Applied due to lack of prevalence data.
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: no specific information on a mutational hotspot or absence of benign variation at this site. Therefore, this criterion is not applied at 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: it is not found 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: JAK2-associated disease is dominant and no trans-phase data. Therefore, this criterion is not applied at Not Applied.
PM4 (Moderate)
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: H538_K539delinsL results in net deletion of two amino acids and insertion of one, altering protein length. Therefore, this criterion is applied at Moderate strength because the variant causes a protein length change.
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 an in-frame indel, not a novel missense change. Therefore, this criterion is not applied at 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'. The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied at Not Applied.
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 family segregation data. Therefore, this criterion is not applied at 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 evidence for this variant shows: it is an in-frame indel, not a missense variant. Therefore, this criterion is not applied at 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/product'. The evidence for this variant shows: in silico predictions are benign and SpliceAI score is 0. Therefore, this criterion is not applied at Not Applied because computational evidence does not support a deleterious effect.
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 detailed phenotype or family history provided. Therefore, this criterion is not applied at 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'. The evidence for this variant shows: no such reports in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for disorder'. The evidence for this variant shows: absent from populations (MAF=0%). Therefore, this criterion is not applied at Not Applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected'. The evidence for this variant shows: no data from healthy cohorts. Therefore, this criterion is not applied at Not Applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect'. The evidence for this variant shows: functional studies indicate a damaging gain-of-function effect. Therefore, this criterion is not applied at Not Applied.
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 family segregation data. Therefore, this criterion is not applied at Not Applied.
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 an in-frame indel in JAK2, not a missense variant. Therefore, this criterion is not applied at Not Applied.
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 co-occurrence with other variants. Therefore, this criterion is not applied at 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 evidence for this variant shows: the altered region is not a repetitive sequence. Therefore, this criterion is not applied at 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 for this variant shows: computational predictions are benign and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because in silico evidence indicates no deleterious effect.
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 such alternate molecular findings. Therefore, this criterion is not applied at Not Applied.
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 such reports. Therefore, this criterion is not applied at Not Applied.
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 not synonymous. Therefore, this criterion is not applied at Not Applied.