9-4988761-C-T

Variant names:

• chr9-4988761-C-T
• rs7849191
• NM_004972.4:c.-26+2739C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004972.4(JAK2):​c.-26+2739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 151,964 control chromosomes in the GnomAD database, including 21,050 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 0.50 (21050 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• thrombocythemia 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.-26+2739C>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.-26+2739C>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.-26+3588C>T		intron	N/A	NP_001309124.1	O60674

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.-26+2739C>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.-26+2739C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.-26+2739C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75423 AN: 151846 Hom.: 21005 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.497 AC: 75532 AN: 151964 Hom.: 21050 Cov.: 32 AF XY: 0.490 AC XY: 36370 AN XY: 74258

African (AFR) AF: 0.770 AC: 31931 AN: 41454

American (AMR) AF: 0.390 AC: 5952 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2080 AN: 5168

South Asian (SAS) AF: 0.370 AC: 1784 AN: 4818

European-Finnish (FIN) AF: 0.374 AC: 3942 AN: 10534

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27445 AN: 67926

Other (OTH) AF: 0.446 AC: 941 AN: 2108

Alfa AF: 0.437 Hom.: 8036

Bravo AF: 0.513

Asia WGS AF: 0.408 AC: 1420 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	4.6
DANN	Benign	0.54
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7849191; hg19: chr9-4988761;