chr9-5072541-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBS2_Supporting

The NM_004972.4(JAK2):c.1691G>T(p.Arg564Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,608,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.59

Variant links:

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]

JAK2 links:

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]

INSL6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000687 (100/1455928) while in subpopulation MID AF= 0.000522 (3/5744). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 55 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4 link	c.1691G>T	p.Arg564Leu	missense_variant	Exon 13 of 25	ENST00000381652.4	NP_004963.1	O60674

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4 link	c.1691G>T	p.Arg564Leu	missense_variant	Exon 13 of 25	1	NM_004972.4	ENSP00000371067.4		O60674
JAK2	ENST00000636127.1 link	c.1691G>T	p.Arg564Leu	missense_variant	Exon 13 of 16	5		ENSP00000489812.1		A0A1B0GTR9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000641

AC:

AN:

249532

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

134904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000687

AC:

100

AN:

1455928

Hom.:

Cov.:

AF XY:

0.0000760

AC XY:

AN XY:

724030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000821

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000686

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000977

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The JAK2 p.Arg564Leu variant was identified in the literature in 3 of 20,000 samples from patients with suspected Myeloproliferative Neoplasias (Ma_2009_PMID:19074595). The variant was also identified in dbSNP (ID: rs368927897) and ClinVar (classified as likely pathogenic by Database of Curated Mutations (DoCM) for Myeloproliferative disorder as a somatic mutation). The variant was identified in control databases in 17 of 280934 chromosomes at a frequency of 0.00006051 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 3 of 10314 chromosomes (freq: 0.000291), European (non-Finnish) in 12 of 128456 chromosomes (freq: 0.000093) and South Asian in 2 of 30264 chromosomes (freq: 0.000066), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Arg564 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2023	Identified in blood and/or bone marrow samples from individuals with myeloproliferative neoplasms (PMID: 19074595, 30811597, 36810551); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24381227, 36810551, 19744331, 19074595, 30811597) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 564 of the JAK2 protein (p.Arg564Leu). This variant is present in population databases (rs368927897, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with JAK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 376706). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt JAK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

JAK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2024

The JAK2 c.1691G>T variant is predicted to result in the amino acid substitution p.Arg564Leu. This variant has been reported in patients with chronic myeloproliferative neoplasias (Ma et al. 2009. PubMed ID: 19074595). In addition, another variant (c.1691G>A) affecting the same amino acid (p.Arg564Gln) has been reported in familial essential thrombocytosis (Etheridge et al. 2014. PubMed ID: 24381227). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.27

.;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

.;N

REVEL

Pathogenic

0.67

Sift

Benign

0.43

.;T

Sift4G

Benign

0.33

.;T

Polyphen

1.0

.;D

Vest4

0.85

MVP

0.93

MPC

0.82

ClinPred

0.45

GERP RS

4.8

Varity_R

0.57

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over