rs12335546

Variant names:

• chr9-5072182-C-T
• rs12335546
• NM_004972.4:c.1642-310C>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.1642-310C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 151,938 control chromosomes in the GnomAD database, including 8,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (8930 hom., cov: 32)
• Consequence: JAK2 NM_004972.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.467
• Publications: 5 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=-0.9).
• BP6: Variant 9-5072182-C-T is Benign according to our data. Variant chr9-5072182-C-T is described in ClinVar as Benign. ClinVar VariationId is 1280967.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 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.1642-310C>T		intron	N/A	NP_004963.1
	JAK2	NM_001322194.2		c.1642-310C>T		intron	N/A	NP_001309123.1
	JAK2	NM_001322195.2		c.1642-310C>T		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.1642-310C>T		intron	N/A	ENSP00000371067.4
	JAK2	ENST00000636127.1	TSL:5	c.1642-310C>T		intron	N/A	ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50719 AN: 151820 Hom.: 8917 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.334 AC: 50775 AN: 151938 Hom.: 8930 Cov.: 32 AF XY: 0.336 AC XY: 24985 AN XY: 74266

African (AFR) AF: 0.458 AC: 18974 AN: 41454

American (AMR) AF: 0.318 AC: 4853 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3470

East Asian (EAS) AF: 0.270 AC: 1395 AN: 5168

South Asian (SAS) AF: 0.331 AC: 1595 AN: 4820

European-Finnish (FIN) AF: 0.329 AC: 3479 AN: 10568

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18582 AN: 67882

Other (OTH) AF: 0.324 AC: 682 AN: 2108

Alfa AF: 0.309 Hom.: 1543

Bravo AF: 0.334

Asia WGS AF: 0.326 AC: 1130 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.91
DANN	Benign	0.32
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12335546; hg19: chr9-5072182;