rs62637626

Variant names:

• chr9-5126443-T-A
• rs62637626
• NM_004972.4:c.3288T>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:3 O:1
• Conservation: PhyloP100: 0.427
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 526 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.3288T>A	p.Asp1096Glu	missense	Exon 24 of 25	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3288T>A	p.Asp1096Glu	missense	Exon 24 of 25	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3288T>A	p.Asp1096Glu	missense	Exon 23 of 24	NP_001309124.1	O60674

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.3288T>A	p.Asp1096Glu	missense	Exon 24 of 25	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3288T>A	p.Asp1096Glu	missense	Exon 24 of 25	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3288T>A	p.Asp1096Glu	missense	Exon 24 of 25	ENSP00000540380.1

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

GnomAD2 exomes AF: 0.000954 AC: 232 AN: 243216 AF XY: 0.000692

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 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

African (AFR) AF: 0.0148 AC: 486 AN: 32732

American (AMR) AF: 0.000418 AC: 18 AN: 43058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 84184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5704

European-Non Finnish (NFE) AF: 0.00000455 AC: 5 AN: 1098808

Other (OTH) AF: 0.000502 AC: 30 AN: 59714

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

African (AFR) AF: 0.0125 AC: 518 AN: 41520

American (AMR) AF: 0.000394 AC: 6 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67620

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.43
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs62637626; hg19: chr9-5126443;