chr9-5081780-G-A

Position:

chr9-5081780-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004972.4(JAK2):c.2490G>A(p.Leu830Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,603,698 control chromosomes in the GnomAD database, including 217,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L830L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.61 ( 30333 hom., cov: 32)

Exomes 𝑓: 0.50 ( 187117 hom. )

Consequence

JAK2
NM_004972.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.475

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:

JAK2 (HGNC:):

JAK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 9-5081780-G-A is Benign according to our data. Variant chr9-5081780-G-A is described in ClinVar as [Benign]. Clinvar id is 367129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-5081780-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.475 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK2	NM_004972.4 linkuse as main transcript	c.2490G>A	p.Leu830Leu	synonymous_variant	19/25	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4 linkuse as main transcript	c.2490G>A	p.Leu830Leu	synonymous_variant	19/25	1	NM_004972.4	ENSP00000371067.4		O60674

Frequencies

GnomAD3 genomes

AF:

0.608

AC:

92386

AN:

151948

Hom.:

30292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.872

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.585

Gnomad EAS

AF:

0.436

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.545

Gnomad NFE

AF:

0.493

Gnomad OTH

AF:

0.586

GnomAD3 exomes

AF:

0.527

AC:

132377

AN:

251286

Hom.:

36214

AF XY:

0.521

AC XY:

70827

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.882

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.437

Gnomad SAS exome

AF:

0.489

Gnomad FIN exome

AF:

0.558

Gnomad NFE exome

AF:

0.498

Gnomad OTH exome

AF:

0.538

GnomAD4 exome

AF:

0.502

AC:

729417

AN:

1451630

Hom.:

187117

Cov.:

AF XY:

0.501

AC XY:

362214

AN XY:

722864

show subpopulations

Gnomad4 AFR exome

AF:

0.886

Gnomad4 AMR exome

AF:

0.504

Gnomad4 ASJ exome

AF:

0.586

Gnomad4 EAS exome

AF:

0.414

Gnomad4 SAS exome

AF:

0.493

Gnomad4 FIN exome

AF:

0.558

Gnomad4 NFE exome

AF:

0.488

Gnomad4 OTH exome

AF:

0.532

GnomAD4 genome

AF:

0.608

AC:

92483

AN:

152068

Hom.:

30333

Cov.:

AF XY:

0.607

AC XY:

45115

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.872

Gnomad4 AMR

AF:

0.544

Gnomad4 ASJ

AF:

0.585

Gnomad4 EAS

AF:

0.437

Gnomad4 SAS

AF:

0.510

Gnomad4 FIN

AF:

0.553

Gnomad4 NFE

AF:

0.493

Gnomad4 OTH

AF:

0.588

Alfa

AF:

0.518

Hom.:

31076

Bravo

AF:

0.616

Asia WGS

AF:

0.535

AC:

1859

AN:

3478

EpiCase

AF:

0.504

EpiControl

AF:

0.502

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	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.10

DANN

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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