NM_004972.4:c.188T>C

Variant names:

• chr9-5022175-T-C
• rs1211921813
• NM_004972.4:c.188T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004972.4(JAK2):​c.188T>C​(p.Val63Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17180851).

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.188T>C	p.Val63Ala	missense	Exon 3 of 25	NP_004963.1	O60674
	JAK2	NM_001322198.2		c.-933T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 25	NP_001309127.1
	JAK2	NM_001322199.2		c.-933T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 25	NP_001309128.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK2	ENST00000381652.4	TSL:1 MANE Select	c.188T>C	p.Val63Ala	missense	Exon 3 of 25	ENSP00000371067.4	O60674
	JAK2	ENST00000870320.1		c.188T>C	p.Val63Ala	missense	Exon 3 of 25	ENSP00000540379.1
	JAK2	ENST00000870321.1		c.188T>C	p.Val63Ala	missense	Exon 3 of 25	ENSP00000540380.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251406 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.11
Sift	Benign	0.063	T
Sift4G	Uncertain	0.060	T
Polyphen		0.012	B
Vest4		0.26
MutPred		0.44		Gain of glycosylation at S59 (P = 0.0945)
MVP		0.71
MPC		0.25
ClinPred		0.26	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.54
Mutation Taster		=45/55	disease causing

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: rs1211921813; hg19: chr9-5022175;