rs2230722

chr9-5050706-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004972.4(JAK2):c.489C>T(p.His163=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,611,558 control chromosomes in the GnomAD database, including 79,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9846 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69592 hom.)
• Consequence: JAK2 NM_004972.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.419

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 9-5050706-C-T is Benign according to our data. Variant chr9-5050706-C-T is described in ClinVar as [Benign]. Clinvar id is 367122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-5050706-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.489C>T	p.His163=	synonymous_variant	6/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.489C>T	p.His163=	synonymous_variant	6/25	1	NM_004972.4	P1
JAK2	ENST00000636127.1	c.489C>T	p.His163=	synonymous_variant	6/16	5

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53534 AN: 151754 Hom.: 9837 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.348

GnomAD3 exomes AF: 0.322 AC: 80745 AN: 250726 Hom.: 13270 AF XY: 0.321 AC XY: 43448 AN XY: 135536

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.274

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.306 AC: 446694 AN: 1459684 Hom.: 69592 Cov.: 33 AF XY: 0.306 AC XY: 222429 AN XY: 726226

Gnomad4 AFR exome AF: 0.477

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.353 AC: 53580 AN: 151874 Hom.: 9846 Cov.: 32 AF XY: 0.354 AC XY: 26240 AN XY: 74212

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.341

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.349

Alfa AF: 0.330 Hom.: 4669

Bravo AF: 0.353

Asia WGS AF: 0.326 AC: 1133 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.2
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2230722; hg19: chr9-5050706; COSMIC: COSV67575449;