rs12339666

Variant names:

• chr9-5063296-G-T
• rs12339666
• NM_004972.4:c.1057-1587G>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.1057-1587G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,034 control chromosomes in the GnomAD database, including 9,252 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 0.34 (9252 hom., cov: 33)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.596
• Publications: 20 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.467 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.1057-1587G>T		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.1057-1587G>T		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.1057-1587G>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.1057-1587G>T		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.1057-1587G>T		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.1057-1587G>T		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51303 AN: 151916 Hom.: 9233 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.338 AC: 51372 AN: 152034 Hom.: 9252 Cov.: 33 AF XY: 0.340 AC XY: 25274 AN XY: 74316

African (AFR) AF: 0.473 AC: 19620 AN: 41478

American (AMR) AF: 0.320 AC: 4889 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 876 AN: 3466

East Asian (EAS) AF: 0.269 AC: 1398 AN: 5190

South Asian (SAS) AF: 0.318 AC: 1533 AN: 4816

European-Finnish (FIN) AF: 0.333 AC: 3513 AN: 10542

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.273 AC: 18530 AN: 67956

Other (OTH) AF: 0.329 AC: 694 AN: 2110

Alfa AF: 0.296 Hom.: 9371

Bravo AF: 0.338

Asia WGS AF: 0.322 AC: 1118 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.75
PhyloP100		0.60
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: rs12339666; hg19: chr9-5063296;