rs2230724

Variant names:

• chr9-5081780-G-A
• rs2230724
• NM_004972.4:c.2490G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-5081780-G-A
• chr9-5081780-G-C
• chr9-5081780-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004972.4(JAK2):​c.2490G>A​(p.Leu830Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,603,698 control chromosomes in the GnomAD database, including 217,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L830L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (30333 hom., cov: 32)
  • Exomes 𝑓: 0.50 (187117 hom.)
• Consequence: JAK2 NM_004972.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.475
• Publications: 59 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-5081780-G-A is Benign according to our data. Variant chr9-5081780-G-A is described in ClinVar as Benign. ClinVar VariationId is 367129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.475 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

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.2490G>A	p.Leu830Leu	synonymous	Exon 19 of 25	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.2490G>A	p.Leu830Leu	synonymous	Exon 19 of 25	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.2490G>A	p.Leu830Leu	synonymous	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.2490G>A	p.Leu830Leu	synonymous	Exon 19 of 25	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.2490G>A	p.Leu830Leu	synonymous	Exon 19 of 25	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.2490G>A	p.Leu830Leu	synonymous	Exon 19 of 25	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92386 AN: 151948 Hom.: 30292 Cov.: 32

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.527 AC: 132377 AN: 251286 AF XY: 0.521

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.498

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.502 AC: 729417 AN: 1451630 Hom.: 187117 Cov.: 30 AF XY: 0.501 AC XY: 362214 AN XY: 722864

African (AFR) AF: 0.886 AC: 29427 AN: 33214

American (AMR) AF: 0.504 AC: 22526 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 15284 AN: 26070

East Asian (EAS) AF: 0.414 AC: 16405 AN: 39608

South Asian (SAS) AF: 0.493 AC: 42435 AN: 86030

European-Finnish (FIN) AF: 0.558 AC: 29765 AN: 53388

Middle Eastern (MID) AF: 0.534 AC: 3071 AN: 5750

European-Non Finnish (NFE) AF: 0.488 AC: 538567 AN: 1102826

Other (OTH) AF: 0.532 AC: 31937 AN: 60054

GnomAD4 genome AF: 0.608 AC: 92483 AN: 152068 Hom.: 30333 Cov.: 32 AF XY: 0.607 AC XY: 45115 AN XY: 74322

African (AFR) AF: 0.872 AC: 36198 AN: 41504

American (AMR) AF: 0.544 AC: 8313 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2032 AN: 3472

East Asian (EAS) AF: 0.437 AC: 2260 AN: 5176

South Asian (SAS) AF: 0.510 AC: 2460 AN: 4826

European-Finnish (FIN) AF: 0.553 AC: 5830 AN: 10540

Middle Eastern (MID) AF: 0.514 AC: 150 AN: 292

European-Non Finnish (NFE) AF: 0.493 AC: 33469 AN: 67952

Other (OTH) AF: 0.588 AC: 1238 AN: 2106

Alfa AF: 0.531 Hom.: 81454

Bravo AF: 0.616

Asia WGS AF: 0.535 AC: 1859 AN: 3478

EpiCase AF: 0.504

EpiControl AF: 0.502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.10
DANN	Benign	0.63
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230724; hg19: chr9-5081780; COSMIC: COSV67575445; COSMIC: COSV67575445;