rs150221602

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004972.4(JAK2):c.2538G>C(p.Glu846Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000855 in 1,613,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 0.609

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]

JAK2 links:

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]

INSL6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-5081828-G-C is Benign according to our data. Variant chr9-5081828-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134553.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000519 (79/152182) while in subpopulation NFE AF= 0.000985 (67/68024). AF 95% confidence interval is 0.000795. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.2538G>C	p.Glu846Asp	missense_variant	Exon 19 of 25	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4 link	c.2538G>C	p.Glu846Asp	missense_variant	Exon 19 of 25	1	NM_004972.4	ENSP00000371067.4		O60674

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000422

AC:

106

AN:

251344

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.000712

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000890

AC:

1301

AN:

1461414

Hom.:

Cov.:

AF XY:

0.000818

AC XY:

595

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000843

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000519

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000882

Hom.:

Bravo

AF:

0.000465

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the published literature in association with erythrocytosis (PMID: 27389715, 37246471, 35764421, 37239426); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 27389715, 37239426, 37246471, 35764421, 34482403) -

not specified

Uncertain:1Other:1

Dec 16, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the JAK2 gene demonstrated a sequence change, c.2538G>C, in exon 19 that results in an amino acid change, p.Glu846Asp. This sequence change has been described in the gnomAD database with a frequency of 0.076% in the non-Finnish European subpopulation (dbSNP rs150221602). The p.Glu846Asp change affects a highly 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.Glu846Asp substitution. This sequence has been previously described as a germline variant in individuals with myeloproliferative disorders in either the heterozygous or compound heterozygous state (PMID: 30259120, 273897150). An experimental study using a cellular model demonstrated that p.Glu846Asp is a weakly activating mutation (PMID: 273897150). Due to insufficient evidences, the clinical significance of the p.Glu846Asp change remains unknown at this time. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.46

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.54

Sift

Uncertain

0.019

Sift4G

Uncertain

0.049

Polyphen

0.31

Vest4

0.86

MutPred

0.34

Loss of ubiquitination at K850 (P = 0.0924);

MVP

0.92

MPC

0.20

ClinPred

0.064

GERP RS

0.012

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.68

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over