9-5126343-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004972.4(JAK2):c.3188G>A(p.Arg1063His) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,600,698 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (41 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 4.23

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01177606).
• BP6: Variant 9-5126343-G-A is Benign according to our data. Variant chr9-5126343-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (742/151770) while in subpopulation NFE AF= 0.00757 (512/67608). AF 95% confidence interval is 0.00703. There are 5 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 742 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.3188G>A	p.Arg1063His	missense_variant	24/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.3188G>A	p.Arg1063His	missense_variant	24/25	1	NM_004972.4	P1
INSL6	ENST00000649639.1	c.*11-1832C>T		intron_variant
JAK2	ENST00000487310.1	n.379G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 742 AN: 151652 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00329

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00437 AC: 1063 AN: 243412 Hom.: 7 AF XY: 0.00432 AC XY: 569 AN XY: 131584

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.000819

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00544 AC: 7888 AN: 1448928 Hom.: 41 Cov.: 28 AF XY: 0.00547 AC XY: 3944 AN XY: 720816

Gnomad4 AFR exome AF: 0.000760

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000891

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.00489 AC: 742 AN: 151770 Hom.: 5 Cov.: 32 AF XY: 0.00461 AC XY: 342 AN XY: 74214

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00757

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00511 Hom.: 6

Bravo AF: 0.00365

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00432 AC: 525

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00644

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	JAK2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	This variant is associated with the following publications: (PMID: 32172663, 30377194, 27389715, 23670291, 31135094, 19643476, 29296762) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2023	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 18, 2021	- -

JAK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary myelofibrosis;C0023467:Acute myeloid leukemia;C0032463:Acquired polycythemia vera;C0856761:Budd-Chiari syndrome;C3281125:Thrombocythemia 3;C4551637:Primary familial polycythemia due to EPO receptor mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.0072
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.93	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.28
Sift	Benign	0.058	T
Sift4G	Benign	0.083	T
Polyphen		0.060	B
Vest4		0.82
MVP		0.76
MPC		0.51
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.46

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: rs41316003; hg19: chr9-5126343; COSMIC: COSV67623251;