9-5126684-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004972.4(JAK2):c.3292A>G(p.Ile1098Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000276 in 1,448,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: JAK2 NM_004972.4 missense, splice_region
• Scores: Splicing: ADA: 0.00009386
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21297061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.3292A>G	p.Ile1098Val	missense_variant, splice_region_variant	25/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.3292A>G	p.Ile1098Val	missense_variant, splice_region_variant	25/25	1	NM_004972.4	P1
INSL6	ENST00000649639.1	c.*11-2173T>C		intron_variant
JAK2	ENST00000487310.1	n.483A>G		splice_region_variant, non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448452 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 720996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

This variant has not been reported in the literature in individuals affected with JAK2-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1098 of the JAK2 protein (p.Ile1098Val). This variant is not present in population databases (gnomAD no frequency). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Benign	0.44
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.54		Gain of catalytic residue at I1098 (P = 0.1329);
MVP		0.58
MPC		0.16
ClinPred		0.77	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.026
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: rs1824020343; hg19: chr9-5126684;