rs1237113183

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004972.4(JAK2):​c.226G>A​(p.Gly76Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,334 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G76C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

JAK2
NM_004972.4 missense, splice_region

Scores

1
8
10
Splicing: ADA: 0.9999
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.24

Publications

0 publications found
Variant links:
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]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAK2NM_004972.4 linkc.226G>A p.Gly76Ser missense_variant, splice_region_variant Exon 3 of 25 ENST00000381652.4 NP_004963.1 O60674

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAK2ENST00000381652.4 linkc.226G>A p.Gly76Ser missense_variant, splice_region_variant Exon 3 of 25 1 NM_004972.4 ENSP00000371067.4 O60674
JAK2ENST00000636127.1 linkc.226G>A p.Gly76Ser missense_variant, splice_region_variant Exon 3 of 16 5 ENSP00000489812.1 A0A1B0GTR9
JAK2ENST00000476574.5 linkc.*148G>A downstream_gene_variant 3 ENSP00000490624.1 A0A1B0GVR5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1457334
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
725270
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33334
American (AMR)
AF:
0.00
AC:
0
AN:
44622
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39652
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86044
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53340
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1108222
Other (OTH)
AF:
0.00
AC:
0
AN:
60250
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.011
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
.;D
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.52
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
.;L
PhyloP100
7.2
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.9
.;D
REVEL
Benign
0.22
Sift
Benign
0.16
.;T
Sift4G
Benign
0.21
.;T
Polyphen
0.38
.;B
Vest4
0.60
MutPred
0.68
Gain of ubiquitination at K73 (P = 0.086);Gain of ubiquitination at K73 (P = 0.086);
MVP
0.58
MPC
0.19
ClinPred
0.86
D
GERP RS
5.6
Varity_R
0.62
gMVP
0.55
Mutation Taster
=27/73
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1237113183; hg19: chr9-5022213; API