rs7032785

Variant names:

• chr9-5042046-C-T
• rs7032785
• NM_004972.4:c.351-2357C>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.351-2357C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 293,396 control chromosomes in the GnomAD database, including 50,196 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 0.62 (31146 hom., cov: 33)
  • Exomes 𝑓: 0.51 (19050 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 3 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]

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]

CSNK1G2P1 (HGNC:49739): (casein kinase 1 gamma 2 pseudogene 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 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.351-2357C>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.351-2357C>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.351-2357C>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.351-2357C>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.351-2357C>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.351-2357C>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93750 AN: 151838 Hom.: 31098 Cov.: 33

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.588

GnomAD4 exome AF: 0.509 AC: 71929 AN: 141442 Hom.: 19050 AF XY: 0.505 AC XY: 39930 AN XY: 78994

African (AFR) AF: 0.889 AC: 2290 AN: 2576

American (AMR) AF: 0.518 AC: 3184 AN: 6148

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 1776 AN: 3002

East Asian (EAS) AF: 0.432 AC: 1884 AN: 4358

South Asian (SAS) AF: 0.484 AC: 13005 AN: 26894

European-Finnish (FIN) AF: 0.558 AC: 3387 AN: 6070

Middle Eastern (MID) AF: 0.537 AC: 1154 AN: 2148

European-Non Finnish (NFE) AF: 0.498 AC: 41410 AN: 83110

Other (OTH) AF: 0.538 AC: 3839 AN: 7136

GnomAD4 genome AF: 0.618 AC: 93855 AN: 151954 Hom.: 31146 Cov.: 33 AF XY: 0.616 AC XY: 45747 AN XY: 74242

African (AFR) AF: 0.880 AC: 36510 AN: 41500

American (AMR) AF: 0.551 AC: 8419 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2072 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2273 AN: 5120

South Asian (SAS) AF: 0.513 AC: 2471 AN: 4818

European-Finnish (FIN) AF: 0.565 AC: 5929 AN: 10502

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34257 AN: 67956

Other (OTH) AF: 0.590 AC: 1243 AN: 2106

Alfa AF: 0.590 Hom.: 3577

Bravo AF: 0.626

Asia WGS AF: 0.548 AC: 1904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		-2.4
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: rs7032785; hg19: chr9-5042046;