9-4985601-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004972.4(JAK2):c.-138C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
JAK2
NM_004972.4 5_prime_UTR
NM_004972.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0450
Publications
1 publications found
Genes affected
JAK2 (HGNC:6192): (Janus kinase 2) This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. Mutations in this gene are associated with numerous inflammatory diseases and malignancies. This gene is a downstream target of the pleiotropic cytokine IL6 that is produced by B cells, T cells, dendritic cells and macrophages to produce an immune response or inflammation. Disregulation of the IL6/JAK2/STAT3 signalling pathways produces increased cellular proliferation and myeloproliferative neoplasms of hematopoietic stem cells. A nonsynonymous mutation in the pseudokinase domain of this gene disrupts the domains inhibitory effect and results in constitutive tyrosine phosphorylation activity and hypersensitivity to cytokine signalling. This gene and the IL6/JAK2/STAT3 signalling pathway is a therapeutic target for the treatment of excessive inflammatory responses to viral infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]
JAK2 Gene-Disease associations (from GenCC):
- thrombocythemia 3Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- familial thrombocytosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAK2 | ENST00000381652.4 | c.-138C>T | 5_prime_UTR_variant | Exon 1 of 25 | 1 | NM_004972.4 | ENSP00000371067.4 | |||
JAK2 | ENST00000636127.1 | c.-108-339C>T | intron_variant | Intron 1 of 15 | 5 | ENSP00000489812.1 | ||||
JAK2 | ENST00000476574.5 | c.-108-339C>T | intron_variant | Intron 1 of 2 | 3 | ENSP00000490624.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 242Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 168
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
242
Hom.:
Cov.:
0
AF XY:
AC XY:
0
AN XY:
168
African (AFR)
AF:
AC:
0
AN:
2
American (AMR)
AC:
0
AN:
0
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
2
East Asian (EAS)
AF:
AC:
0
AN:
70
South Asian (SAS)
AC:
0
AN:
0
European-Finnish (FIN)
AC:
0
AN:
0
Middle Eastern (MID)
AF:
AC:
0
AN:
2
European-Non Finnish (NFE)
AF:
AC:
0
AN:
162
Other (OTH)
AF:
AC:
0
AN:
4
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Budd-Chiari syndrome Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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