rs200018153

Positions:

• chr9-5065000-G-A
• chr9-5065000-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001322198.2(JAK2):​c.-42G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000192 in 1,607,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: JAK2 NM_001322198.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 4.06

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]

JAK2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063711703).
• BP6: Variant 9-5065000-G-A is Benign according to our data. Variant chr9-5065000-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134564.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-5065000-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000368 (56/152294) while in subpopulation EAS AF= 0.00867 (45/5188). AF 95% confidence interval is 0.00666. There are 1 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK2	NM_004972.4	c.1174G>A	p.Val392Met	missense_variant	9/25	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.1174G>A	p.Val392Met	missense_variant	9/25	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.1174G>A	p.Val392Met	missense_variant	9/16	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000638 AC: 157 AN: 246256 Hom.: 0 AF XY: 0.000653 AC XY: 87 AN XY: 133172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000606

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00826

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 252 AN: 1454880 Hom.: 0 Cov.: 29 AF XY: 0.000177 AC XY: 128 AN XY: 723712

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000913

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00394

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.000799

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74470

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000298

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.34	.;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0070	.;D
Polyphen		0.98	.;D
Vest4		0.31
MVP		0.75
MPC		0.37
ClinPred		0.058	T
GERP RS		2.2
Varity_R		0.089
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200018153; hg19: chr9-5065000; COSMIC: COSV67587963;