rs7046736

Variant names:

• chr9-5015732-C-A
• rs7046736
• NM_004972.4:c.-25-6231C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-5015732-C-A
• chr9-5015732-C-G

Variant summary

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

The NM_004972.4(JAK2):​c.-25-6231C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,800 control chromosomes in the GnomAD database, including 12,375 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 0.39 (12375 hom., cov: 31)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690
• Publications: 13 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 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.-25-6231C>A		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.-25-6231C>A		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.-25-6231C>A		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.-25-6231C>A		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.-25-6231C>A		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.-25-6231C>A		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58468 AN: 151682 Hom.: 12350 Cov.: 31

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.364

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

GnomAD4 genome AF: 0.386 AC: 58545 AN: 151800 Hom.: 12375 Cov.: 31 AF XY: 0.389 AC XY: 28864 AN XY: 74204

African (AFR) AF: 0.568 AC: 23517 AN: 41392

American (AMR) AF: 0.348 AC: 5305 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 948 AN: 3472

East Asian (EAS) AF: 0.338 AC: 1743 AN: 5160

South Asian (SAS) AF: 0.406 AC: 1952 AN: 4812

European-Finnish (FIN) AF: 0.378 AC: 3978 AN: 10510

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.295 AC: 19992 AN: 67882

Other (OTH) AF: 0.366 AC: 772 AN: 2112

Alfa AF: 0.227 Hom.: 510

Bravo AF: 0.386

Asia WGS AF: 0.415 AC: 1439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.50
PhyloP100		0.069
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: rs7046736; hg19: chr9-5015732; COSMIC: COSV67594627;