chr9-5126321-G-GC

Variant names:

• chr9-5126321-G-GC
• rs533264615
• NM_004972.4:c.3178-12_3178-11insC

Variant summary

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

The NM_004972.4(JAK2):​c.3178-12_3178-11insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,545,100 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.125
• Publications: 0 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 9-5126321-G-GC is Benign according to our data. Variant chr9-5126321-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1319235.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00148 (225/151780) while in subpopulation NFE AF = 0.00279 (189/67650). AF 95% confidence interval is 0.00247. There are 1 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 225 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.3178-12_3178-11insC		intron	N/A	NP_004963.1	O60674
	JAK2	NM_001322194.2		c.3178-12_3178-11insC		intron	N/A	NP_001309123.1	O60674
	JAK2	NM_001322195.2		c.3178-12_3178-11insC		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.3178-12_3178-11insC		intron	N/A	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.3178-12_3178-11insC		intron	N/A	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.3178-12_3178-11insC		intron	N/A	ENSP00000540380.1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 151662 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00233 AC: 536 AN: 230054 AF XY: 0.00234

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.0000339

Gnomad ASJ exome AF: 0.000659

Gnomad EAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00198

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00242 AC: 3365 AN: 1393320 Hom.: 6 Cov.: 22 AF XY: 0.00230 AC XY: 1602 AN XY: 695366

African (AFR) AF: 0.000226 AC: 7 AN: 31032

American (AMR) AF: 0.000126 AC: 5 AN: 39594

Ashkenazi Jewish (ASJ) AF: 0.000241 AC: 6 AN: 24914

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38694

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80374

European-Finnish (FIN) AF: 0.00268 AC: 142 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00289 AC: 3066 AN: 1062044

Other (OTH) AF: 0.00236 AC: 137 AN: 58040

GnomAD4 genome AF: 0.00148 AC: 225 AN: 151780 Hom.: 1 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74228

African (AFR) AF: 0.000241 AC: 10 AN: 41510

American (AMR) AF: 0.000262 AC: 4 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00279 AC: 189 AN: 67650

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00121

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

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: rs533264615; hg19: chr9-5126321;