9-5126343-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004972.4(JAK2):c.3188G>A(p.Arg1063His) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,600,698 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 41 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 4.23

Publications

64 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]

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01177606).

BP6

Variant 9-5126343-G-A is Benign according to our data. Variant chr9-5126343-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00489 (742/151770) while in subpopulation NFE AF = 0.00757 (512/67608). AF 95% confidence interval is 0.00703. There are 5 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 742 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.3188G>A	p.Arg1063His	missense_variant	Exon 24 of 25	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAK2	ENST00000381652.4 link	c.3188G>A	p.Arg1063His	missense_variant	Exon 24 of 25	1	NM_004972.4	ENSP00000371067.4	O60674
JAK2	ENST00000487310.1 link	n.379G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
INSL6	ENST00000649639.1 link	c.*11-1832C>T		intron_variant	Intron 3 of 3			ENSP00000497955.1	A0A3B3ITZ2

Frequencies

GnomAD3 genomes

AF:

0.00489

AC:

742

AN:

151652

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00329

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00757

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00437

AC:

1063

AN:

243412

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.000886

Gnomad AMR exome

AF:

0.00170

Gnomad ASJ exome

AF:

0.000819

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.0107

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00470

GnomAD4 exome

AF:

0.00544

AC:

7888

AN:

1448928

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

3944

AN XY:

720816

show subpopulations

African (AFR)

AF:

0.000760

AC:

AN:

32882

American (AMR)

AF:

0.00197

AC:

AN:

43164

Ashkenazi Jewish (ASJ)

AF:

0.000891

AC:

AN:

25818

East Asian (EAS)

AF:

0.000153

AC:

AN:

39308

South Asian (SAS)

AF:

0.00249

AC:

210

AN:

84200

European-Finnish (FIN)

AF:

0.0110

AC:

584

AN:

53282

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00603

AC:

6665

AN:

1104628

Other (OTH)

AF:

0.00481

AC:

288

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

327

654

980

1307

1634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00489

AC:

742

AN:

151770

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

342

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41532

American (AMR)

AF:

0.00335

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

3460

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00757

AC:

512

AN:

67608

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00488

Hom.:

Bravo

AF:

0.00365

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00432

AC:

525

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00644

EpiControl

AF:

0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

JAK2: BS1, BS2 -

Jan 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32172663, 30377194, 27389715, 23670291, 31135094, 19643476, 29296762) -

not specified

Benign:1Other:1

May 18, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

JAK2-related disorder

Benign:1

Oct 06, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary myelofibrosis;C0023467:Acute myeloid leukemia;C0032463:Acquired polycythemia vera;C0856761:Budd-Chiari syndrome;C3281125:Thrombocythemia 3;C4551637:Primary familial polycythemia due to EPO receptor mutation

Benign:1

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

0.0072

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.76

M_CAP

Benign

0.031

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.93

PhyloP100

4.2

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.95

REVEL

Benign

0.28

Sift

Benign

0.058

Sift4G

Benign

0.083

Polyphen

0.060

Vest4

0.82

MVP

0.76

MPC

0.51

ClinPred

0.018

GERP RS

5.1

Varity_R

0.27

gMVP

0.46

Mutation Taster

=66/34

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-5126343-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over