rs62637626

chr9-5126443-T-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.3288T>A(p.Asp1096Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,594,448 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.427

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=0.010904133).
• BP6: Variant 9-5126443-T-A is Benign according to our data. Variant chr9-5126443-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 134556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00347 (526/151772) while in subpopulation AFR AF= 0.0125 (518/41520). AF 95% confidence interval is 0.0116. There are 4 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK2	NM_004972.4	c.3288T>A	p.Asp1096Glu	missense_variant	24/25	ENST00000381652.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK2	ENST00000381652.4	c.3288T>A	p.Asp1096Glu	missense_variant	24/25	1	NM_004972.4	P1
INSL6	ENST00000649639.1	c.*11-1932A>T		intron_variant
JAK2	ENST00000487310.1	n.479T>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 524 AN: 151654 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000954 AC: 232 AN: 243216 Hom.: 1 AF XY: 0.000692 AC XY: 91 AN XY: 131464

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000375 AC: 541 AN: 1442676 Hom.: 5 Cov.: 26 AF XY: 0.000335 AC XY: 241 AN XY: 718348

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.000418

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.000502

GnomAD4 genome AF: 0.00347 AC: 526 AN: 151772 Hom.: 4 Cov.: 32 AF XY: 0.00323 AC XY: 240 AN XY: 74226

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00366

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	15
Dann	Benign	0.50
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.018	B
Vest4		0.40
MutPred		0.44		Gain of catalytic residue at D1096 (P = 0.1016);
MVP		0.70
MPC		0.18
ClinPred		0.0046	T
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62637626; hg19: chr9-5126443; COSMIC: COSV104701506;