chr9-5068520-T-C

Position:

• chr9-5068520-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004972.4(JAK2):​c.1327-502T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 152,012 control chromosomes in the GnomAD database, including 8,664 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 0.33 (8664 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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:):

ACMG classification

Verdict is Benign. Variant got -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 = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.1327-502T>C		intron_variant		ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.1327-502T>C		intron_variant		1	NM_004972.4	P1
JAK2	ENST00000636127.1	c.1327-502T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49865 AN: 151894 Hom.: 8648 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.328 AC: 49929 AN: 152012 Hom.: 8664 Cov.: 32 AF XY: 0.331 AC XY: 24573 AN XY: 74298

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.320

Alfa AF: 0.172 Hom.: 316

Bravo AF: 0.329

Asia WGS AF: 0.326 AC: 1133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs3780365; hg19: chr9-5068520; COSMIC: COSV67594744;