NM_004972.4:c.3060-9427C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004972.4(JAK2):c.3060-9427C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 157,228 control chromosomes in the GnomAD database, including 10,802 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 10585 hom., cov: 30)

Exomes 𝑓: 0.26 ( 217 hom. )

Consequence

JAK2
NM_004972.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

Publications

12 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:

IGHEP2 (HGNC:5524): (immunoglobulin heavy constant epsilon P2 (pseudogene))

IGHEP2 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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.3060-9427C>T		intron_variant	Intron 22 of 24	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4 link	c.3060-9427C>T		intron_variant	Intron 22 of 24	1	NM_004972.4	ENSP00000371067.4		O60674
IGHEP2	ENST00000519308.1 link	n.29C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54298

AN:

151482

Hom.:

10574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.287

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.259

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.245

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.334

GnomAD4 exome

AF:

0.258

AC:

1454

AN:

5628

Hom.:

217

Cov.:

AF XY:

0.263

AC XY:

802

AN XY:

3052

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.282

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

AN:

East Asian (EAS)

AF:

0.125

AC:

AN:

South Asian (SAS)

AF:

0.266

AC:

220

AN:

828

European-Finnish (FIN)

AF:

0.275

AC:

564

AN:

2054

Middle Eastern (MID)

AF:

0.273

AC:

AN:

European-Non Finnish (NFE)

AF:

0.248

AC:

540

AN:

2178

Other (OTH)

AF:

0.190

AC:

AN:

290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

AF:

0.359

AC:

54350

AN:

151600

Hom.:

10585

Cov.:

AF XY:

0.358

AC XY:

26539

AN XY:

74106

show subpopulations

African (AFR)

AF:

0.530

AC:

21851

AN:

41218

American (AMR)

AF:

0.335

AC:

5102

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

897

AN:

3468

East Asian (EAS)

AF:

0.260

AC:

1340

AN:

5146

South Asian (SAS)

AF:

0.322

AC:

1547

AN:

4802

European-Finnish (FIN)

AF:

0.334

AC:

3519

AN:

10538

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.281

AC:

19061

AN:

67880

Other (OTH)

AF:

0.335

AC:

705

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1658

3316

4973

6631

8289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.310

Hom.:

22777

Bravo

AF:

0.362

Asia WGS

AF:

0.319

AC:

1106

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.4

(source)

DANN

Benign

0.46

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.99

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over