chr9-5078117-T-C

Variant names:

• chr9-5078117-T-C
• rs1159782
• NM_004972.4:c.1993-189T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004972.4(JAK2):​c.1993-189T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,126 control chromosomes in the GnomAD database, including 4,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (4599 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.912
• Publications: 18 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-5078117-T-C is Benign according to our data. Variant chr9-5078117-T-C is described in ClinVar as Benign. ClinVar VariationId is 1179213.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.1993-189T>C		intron_variant	Intron 15 of 24	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.1993-189T>C		intron_variant	Intron 15 of 24	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.1993-189T>C		intron_variant	Intron 15 of 15	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35813 AN: 152008 Hom.: 4602 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.235 AC: 35809 AN: 152126 Hom.: 4599 Cov.: 32 AF XY: 0.240 AC XY: 17832 AN XY: 74370

African (AFR) AF: 0.129 AC: 5373 AN: 41516

American (AMR) AF: 0.277 AC: 4236 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 890 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1333 AN: 5182

South Asian (SAS) AF: 0.306 AC: 1472 AN: 4816

European-Finnish (FIN) AF: 0.320 AC: 3373 AN: 10556

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18308 AN: 67992

Other (OTH) AF: 0.241 AC: 508 AN: 2110

Alfa AF: 0.256 Hom.: 691

Bravo AF: 0.224

Asia WGS AF: 0.264 AC: 915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.65
PhyloP100		-0.91
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: rs1159782; hg19: chr9-5078117; COSMIC: COSV67594760;