rs2230722

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001322198.2(JAK2):c.-632C>T 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 0.31 in 1,611,558 control chromosomes in the GnomAD database, including 79,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9846 hom., cov: 32)

Exomes 𝑓: 0.31 ( 69592 hom. )

Consequence

JAK2
NM_001322198.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.419

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 made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 9-5050706-C-T is Benign according to our data. Variant chr9-5050706-C-T is described in ClinVar as [Benign]. Clinvar id is 367122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-5050706-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.489C>T	p.His163His	synonymous_variant	Exon 6 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.489C>T	p.His163His	synonymous_variant	Exon 6 of 25	1	NM_004972.4	ENSP00000371067.4		O60674
JAK2	ENST00000636127.1 link	c.489C>T	p.His163His	synonymous_variant	Exon 6 of 16	5		ENSP00000489812.1		A0A1B0GTR9

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53534

AN:

151754

Hom.:

9837

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.334

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.348

GnomAD3 exomes

AF:

0.322

AC:

80745

AN:

250726

Hom.:

13270

AF XY:

0.321

AC XY:

43448

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.320

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.274

Gnomad SAS exome

AF:

0.325

Gnomad FIN exome

AF:

0.339

Gnomad NFE exome

AF:

0.310

Gnomad OTH exome

AF:

0.312

GnomAD4 exome

AF:

0.306

AC:

446694

AN:

1459684

Hom.:

69592

Cov.:

AF XY:

0.306

AC XY:

222429

AN XY:

726226

show subpopulations

Gnomad4 AFR exome

AF:

0.477

Gnomad4 AMR exome

AF:

0.322

Gnomad4 ASJ exome

AF:

0.278

Gnomad4 EAS exome

AF:

0.258

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.337

Gnomad4 NFE exome

AF:

0.299

Gnomad4 OTH exome

AF:

0.315

GnomAD4 genome

AF:

0.353

AC:

53580

AN:

151874

Hom.:

9846

Cov.:

AF XY:

0.354

AC XY:

26240

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.338

Gnomad4 ASJ

AF:

0.272

Gnomad4 EAS

AF:

0.265

Gnomad4 SAS

AF:

0.335

Gnomad4 FIN

AF:

0.341

Gnomad4 NFE

AF:

0.301

Gnomad4 OTH

AF:

0.349

Alfa

AF:

0.330

Hom.:

4669

Bravo

AF:

0.353

Asia WGS

AF:

0.326

AC:

1133

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.304

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

8.2

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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