rs10974947

Variant names:

• chr9-5072846-G-A
• rs10974947
• NM_004972.4:c.1776+220G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-5072846-G-A
• chr9-5072846-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004972.4(JAK2):​c.1776+220G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,046 control chromosomes in the GnomAD database, including 4,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4307 hom., cov: 33)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.226
• Publications: 25 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-5072846-G-A is Benign according to our data. Variant chr9-5072846-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247124.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 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.1776+220G>A		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.1776+220G>A		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.1776+220G>A		intron	N/A	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.1776+220G>A		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.1776+220G>A		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.1776+220G>A		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35521 AN: 151928 Hom.: 4308 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35537 AN: 152046 Hom.: 4307 Cov.: 33 AF XY: 0.232 AC XY: 17267 AN XY: 74318

African (AFR) AF: 0.205 AC: 8517 AN: 41462

American (AMR) AF: 0.211 AC: 3218 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1119 AN: 3468

East Asian (EAS) AF: 0.172 AC: 891 AN: 5192

South Asian (SAS) AF: 0.190 AC: 916 AN: 4824

European-Finnish (FIN) AF: 0.258 AC: 2724 AN: 10554

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17188 AN: 67972

Other (OTH) AF: 0.238 AC: 502 AN: 2106

Alfa AF: 0.243 Hom.: 20559

Bravo AF: 0.230

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.72
DANN	Benign	0.59
PhyloP100		-0.23
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: rs10974947; hg19: chr9-5072846;