rs3824433

Positions:

• chr9-5113577-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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]

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

INSL6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
JAK2	NM_004972.4	c.3060-9427C>T		intron_variant		ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.3060-9427C>T		intron_variant		1	NM_004972.4	ENSP00000371067	P1
IGHEP2	ENST00000519308.1	n.29C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54298 AN: 151482 Hom.: 10574 Cov.: 30

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.: 0 AF XY: 0.263 AC XY: 802 AN XY: 3052

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.359 AC: 54350 AN: 151600 Hom.: 10585 Cov.: 30 AF XY: 0.358 AC XY: 26539 AN XY: 74106

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.335

Alfa AF: 0.293 Hom.: 11647

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
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99

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

LitVar

Other links and lift over

dbSNP: rs3824433; hg19: chr9-5113577; COSMIC: COSV67572034; COSMIC: COSV67572034;