9-5065750-G-C

Variant names:

• chr9-5065750-G-C
• rs12342421
• NM_004972.4:c.1214+710G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004972.4(JAK2):​c.1214+710G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,042 control chromosomes in the GnomAD database, including 4,477 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4477 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.691
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	NM_004972.4	MANE Select	c.1214+710G>C		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.1214+710G>C		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.1214+710G>C		intron	N/A	NP_001309124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.1214+710G>C		intron	N/A	ENSP00000371067.4
	JAK2	ENST00000636127.1	TSL:5	c.1214+710G>C		intron	N/A	ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35152 AN: 151924 Hom.: 4483 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.231 AC: 35150 AN: 152042 Hom.: 4477 Cov.: 32 AF XY: 0.236 AC XY: 17550 AN XY: 74304

African (AFR) AF: 0.125 AC: 5197 AN: 41492

American (AMR) AF: 0.276 AC: 4215 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1331 AN: 5176

South Asian (SAS) AF: 0.302 AC: 1454 AN: 4816

European-Finnish (FIN) AF: 0.327 AC: 3447 AN: 10542

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17835 AN: 67948

Other (OTH) AF: 0.237 AC: 500 AN: 2106

Alfa AF: 0.157 Hom.: 323

Bravo AF: 0.219

Asia WGS AF: 0.261 AC: 905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.32
PhyloP100		-0.69
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: rs12342421; hg19: chr9-5065750; COSMIC: COSV67594738;