chr9-5126542-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004972.4(JAK2):c.3291+96T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 977,320 control chromosomes in the GnomAD database, including 1,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 1071 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 568 hom. )

Consequence

JAK2
NM_004972.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.240

Publications

2 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 9-5126542-T-G is Benign according to our data. Variant chr9-5126542-T-G is described in ClinVar as [Benign]. Clinvar id is 1240578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.3291+96T>G		intron_variant	Intron 24 of 24	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAK2	ENST00000381652.4 link	c.3291+96T>G	intron_variant	Intron 24 of 24	1	NM_004972.4	ENSP00000371067.4	O60674
INSL6	ENST00000649639.1 link	c.*11-2031A>C	intron_variant	Intron 3 of 3			ENSP00000497955.1	A0A3B3ITZ2
JAK2	ENST00000487310.1 link	n.482+96T>G	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0657

AC:

9963

AN:

151628

Hom.:

1066

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000724

Gnomad OTH

AF:

0.0416

GnomAD4 exome

AF:

0.00721

AC:

5951

AN:

825574

Hom.:

568

Cov.:

AF XY:

0.00607

AC XY:

2591

AN XY:

426598

show subpopulations

African (AFR)

AF:

0.237

AC:

4503

AN:

18994

American (AMR)

AF:

0.0133

AC:

401

AN:

30200

Ashkenazi Jewish (ASJ)

AF:

0.000375

AC:

AN:

18652

East Asian (EAS)

AF:

0.00

AC:

AN:

34346

South Asian (SAS)

AF:

0.000840

AC:

AN:

60716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47902

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

4396

European-Non Finnish (NFE)

AF:

0.000551

AC:

315

AN:

571594

Other (OTH)

AF:

0.0160

AC:

620

AN:

38774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

258

516

774

1032

1290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0658

AC:

9986

AN:

151746

Hom.:

1071

Cov.:

AF XY:

0.0639

AC XY:

4742

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.229

AC:

9474

AN:

41460

American (AMR)

AF:

0.0243

AC:

370

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000724

AC:

AN:

67638

Other (OTH)

AF:

0.0412

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

392

785

1177

1570

1962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0584

Hom.:

833

Bravo

AF:

0.0739

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

7.2

(source)

DANN

Benign

0.65

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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chr9-5126542-T-G

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