chr9-5081780-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

59 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 -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 VariationId is 367129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.2490G>A	p.Leu830Leu	synonymous_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.2490G>A	p.Leu830Leu	synonymous_variant	Exon 19 of 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

GnomAD2 exomes

AF:

0.527

AC:

132377

AN:

251286

AF XY:

0.521

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 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

African (AFR)

AF:

0.886

AC:

29427

AN:

33214

American (AMR)

AF:

0.504

AC:

22526

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

15284

AN:

26070

East Asian (EAS)

AF:

0.414

AC:

16405

AN:

39608

South Asian (SAS)

AF:

0.493

AC:

42435

AN:

86030

European-Finnish (FIN)

AF:

0.558

AC:

29765

AN:

53388

Middle Eastern (MID)

AF:

0.534

AC:

3071

AN:

5750

European-Non Finnish (NFE)

AF:

0.488

AC:

538567

AN:

1102826

Other (OTH)

AF:

0.532

AC:

31937

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

16092

32184

48275

64367

80459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15830

31660

47490

63320

79150

<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:

0.608

AC:

92483

AN:

152068

Hom.:

30333

Cov.:

AF XY:

0.607

AC XY:

45115

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.872

AC:

36198

AN:

41504

American (AMR)

AF:

0.544

AC:

8313

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

2032

AN:

3472

East Asian (EAS)

AF:

0.437

AC:

2260

AN:

5176

South Asian (SAS)

AF:

0.510

AC:

2460

AN:

4826

European-Finnish (FIN)

AF:

0.553

AC:

5830

AN:

10540

Middle Eastern (MID)

AF:

0.514

AC:

150

AN:

292

European-Non Finnish (NFE)

AF:

0.493

AC:

33469

AN:

67952

Other (OTH)

AF:

0.588

AC:

1238

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1673

3346

5019

6692

8365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.531

Hom.:

81454

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

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.63

PhyloP100

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(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

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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