chr9-5070227-ATTATC-A

Variant names:

• chr9-5070227-ATTATC-A
• rs56241661
• NM_004972.4:c.1641+179_1641+183delTCTTA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004972.4(JAK2):​c.1641+179_1641+183delTCTTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 151,936 control chromosomes in the GnomAD database, including 4,569 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4569 hom., cov: 23)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 2 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.1641+179_1641+183delTCTTA		intron_variant	Intron 12 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.1641+176_1641+180delTTATC		intron_variant	Intron 12 of 24	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.1641+176_1641+180delTTATC		intron_variant	Intron 12 of 15	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36548 AN: 151818 Hom.: 4576 Cov.: 23

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.241 AC: 36554 AN: 151936 Hom.: 4569 Cov.: 23 AF XY: 0.245 AC XY: 18187 AN XY: 74246

African (AFR) AF: 0.163 AC: 6754 AN: 41496

American (AMR) AF: 0.282 AC: 4307 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 876 AN: 3470

East Asian (EAS) AF: 0.255 AC: 1318 AN: 5174

South Asian (SAS) AF: 0.302 AC: 1457 AN: 4826

European-Finnish (FIN) AF: 0.315 AC: 3314 AN: 10508

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17689 AN: 67892

Other (OTH) AF: 0.250 AC: 526 AN: 2108

Alfa AF: 0.262 Hom.: 658

Bravo AF: 0.232

Asia WGS AF: 0.266 AC: 921 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56241661; hg19: chr9-5070227;