rs150221602

Variant names:

• chr9-5081828-G-C
• rs150221602
• NM_004972.4:c.2538G>C
• JAK2 p.Glu846Asp

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004972.4(JAK2):​c.2538G>C​(p.Glu846Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000855 in 1,613,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (0 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: 0.609
• Publications: 29 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 -9 ACMG points.

• BP6: Variant 9-5081828-G-C is Benign according to our data. Variant chr9-5081828-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134553.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000519 (79/152182) while in subpopulation NFE AF = 0.000985 (67/68024). AF 95% confidence interval is 0.000795. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 79 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.2538G>C	p.Glu846Asp	missense	Exon 19 of 25	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.2538G>C	p.Glu846Asp	missense	Exon 19 of 25	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.2538G>C	p.Glu846Asp	missense	Exon 18 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.2538G>C	p.Glu846Asp	missense	Exon 19 of 25	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.2538G>C	p.Glu846Asp	missense	Exon 19 of 25	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.2538G>C	p.Glu846Asp	missense	Exon 19 of 25	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251344 AF XY: 0.000353

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000890 AC: 1301 AN: 1461414 Hom.: 0 Cov.: 30 AF XY: 0.000818 AC XY: 595 AN XY: 727032

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86234

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1158 AN: 1111644

Other (OTH) AF: 0.00129 AC: 78 AN: 60380

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74362

African (AFR) AF: 0.000121 AC: 5 AN: 41440

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000882 Hom.: 0

Bravo AF: 0.000465

EpiCase AF: 0.000600

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Inherited susceptibility to asthma (1)
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.61
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.049	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.37
Mutation Taster		=8/92	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs150221602;

hg19: chr9-5081828;

COSMIC: COSV101070342;