chr9-5022163-C-G
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_001322198.2(JAK2):c.-945C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
JAK2
NM_001322198.2 5_prime_UTR_premature_start_codon_gain
NM_001322198.2 5_prime_UTR_premature_start_codon_gain
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 0.165
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]
INSL6 (HGNC:6089): (insulin like 6) The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. This gene is preferentially expressed in testis. Its expression in testis is restricted to interstitial cells surrounding seminiferous tubules, which suggests a role in sperm development and fertilization. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.057501882).
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAK2 | ENST00000381652.4 | c.176C>G | p.Ser59Cys | missense_variant | Exon 3 of 25 | 1 | NM_004972.4 | ENSP00000371067.4 | ||
JAK2 | ENST00000636127.1 | c.176C>G | p.Ser59Cys | missense_variant | Exon 3 of 16 | 5 | ENSP00000489812.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152144
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251426Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD3 exomes
AF:
AC:
2
AN:
251426
Hom.:
AF XY:
AC XY:
2
AN XY:
135888
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727208
GnomAD4 exome
AF:
AC:
6
AN:
1461812
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
727208
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
GnomAD4 genome
AF:
AC:
1
AN:
152144
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74326
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 19, 2021 | DNA sequence analysis of the JAK2 gene demonstrated a sequence change, c.176C>G, in exon 3 that results in an amino acid change, p.Ser59Cys. This sequence change has been described in gnomAD with a frequency of 0.020% (dbSNP rs754086152) in the Ashkenazi Jewish sub-population. The p.Ser59Cys change affects a poorly conserved amino acid residue located in a domain of the JAK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser59Cys substitution. This sequence change does not appear to have been previously described in patients with JAK2-related disorders and has also not been described as a known benign sequence change in the JAK2 gene Due to the lack of sufficient evidences, the clinical significance of the p.Ser59Cys change remains unknown at this time. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2024 | The c.176C>G (p.S59C) alteration is located in exon 3 (coding exon 1) of the JAK2 gene. This alteration results from a C to G substitution at nucleotide position 176, causing the serine (S) at amino acid position 59 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L
PrimateAI
Benign
T
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Benign
.;D
Sift4G
Uncertain
.;T
Polyphen
0.10
.;B
Vest4
0.24
MutPred
Loss of glycosylation at S59 (P = 0.0279);Loss of glycosylation at S59 (P = 0.0279);
MVP
0.43
MPC
0.24
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at