rs2230722

Variant names:

• chr9-5050706-C-T
• rs2230722
• NM_004972.4:c.489C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004972.4(JAK2):​c.489C>T​(p.His163His) 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:6
• Conservation: PhyloP100: 0.419
• Publications: 40 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 -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 VariationId is 367122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.489C>T	p.His163His	synonymous_variant	Exon 6 of 25	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.489C>T	p.His163His	synonymous_variant	Exon 6 of 25	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.489C>T	p.His163His	synonymous_variant	Exon 6 of 16	5		ENSP00000489812.1

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

GnomAD2 exomes AF: 0.322 AC: 80745 AN: 250726 AF XY: 0.321

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 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

African (AFR) AF: 0.477 AC: 15936 AN: 33406

American (AMR) AF: 0.322 AC: 14374 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7247 AN: 26106

East Asian (EAS) AF: 0.258 AC: 10217 AN: 39630

South Asian (SAS) AF: 0.328 AC: 28215 AN: 86136

European-Finnish (FIN) AF: 0.337 AC: 18009 AN: 53384

Middle Eastern (MID) AF: 0.318 AC: 1835 AN: 5764

European-Non Finnish (NFE) AF: 0.299 AC: 331873 AN: 1110322

Other (OTH) AF: 0.315 AC: 18988 AN: 60330

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

African (AFR) AF: 0.468 AC: 19359 AN: 41386

American (AMR) AF: 0.338 AC: 5171 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 942 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1366 AN: 5162

South Asian (SAS) AF: 0.335 AC: 1613 AN: 4814

European-Finnish (FIN) AF: 0.341 AC: 3583 AN: 10506

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20468 AN: 67940

Other (OTH) AF: 0.349 AC: 737 AN: 2114

Alfa AF: 0.342 Hom.: 7225

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.2
DANN	Benign	0.61
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2230722; hg19: chr9-5050706; COSMIC: COSV67575449;