9-5065003-C-G

Variant names:

• chr9-5065003-C-G
• rs2230723
• NM_004972.4:c.1177C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004972.4(JAK2):​c.1177C>G​(p.Leu393Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00647 in 1,605,824 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (58 hom.)
• Consequence: JAK2 NM_004972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 2.04
• Publications: 30 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005871594).
• BP6: Variant 9-5065003-C-G is Benign according to our data. Variant chr9-5065003-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134563.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1967/152240) while in subpopulation AFR AF = 0.0263 (1092/41540). AF 95% confidence interval is 0.025. There are 25 homozygotes in GnomAd4. There are 964 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1967 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK2	NM_004972.4	c.1177C>G	p.Leu393Val	missense_variant	Exon 9 of 25	ENST00000381652.4	NP_004963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK2	ENST00000381652.4	c.1177C>G	p.Leu393Val	missense_variant	Exon 9 of 25	1	NM_004972.4	ENSP00000371067.4
JAK2	ENST00000636127.1	c.1177C>G	p.Leu393Val	missense_variant	Exon 9 of 16	5		ENSP00000489812.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1967 AN: 152122 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00766 AC: 1877 AN: 245174 AF XY: 0.00714

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00580 AC: 8427 AN: 1453584 Hom.: 58 Cov.: 29 AF XY: 0.00561 AC XY: 4059 AN XY: 723096

African (AFR) AF: 0.0219 AC: 725 AN: 33136

American (AMR) AF: 0.0150 AC: 653 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 920 AN: 25916

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39334

South Asian (SAS) AF: 0.000426 AC: 36 AN: 84602

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53168

Middle Eastern (MID) AF: 0.0169 AC: 97 AN: 5744

European-Non Finnish (NFE) AF: 0.00476 AC: 5278 AN: 1108022

Other (OTH) AF: 0.0117 AC: 702 AN: 60026

GnomAD4 genome AF: 0.0129 AC: 1967 AN: 152240 Hom.: 25 Cov.: 33 AF XY: 0.0130 AC XY: 964 AN XY: 74436

African (AFR) AF: 0.0263 AC: 1092 AN: 41540

American (AMR) AF: 0.0253 AC: 386 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 67996

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00758 Hom.: 3

Bravo AF: 0.0158

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00731 AC: 887

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK2: BS1, BS2 -

Jul 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4 -

Jun 23, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as a germline alteration in individuals with polycythemia vera or secondary erythrocytosis with or without the acquired V617F variant (PMID: 27647865, 35304527, 38468832); Identified in samples from diffuse large B-cell tumors, BCR-ABL1 negative and JAK2 V617F negative chronic myeloproliferative neoplasms, and head and neck squamous cell carcinomas; however, one study showed no difference in distribution of this variant in patients versus controls, and patient germline samples were not tested (PMID: 22762550, 20417861, 23670291, 33792220); Functional studies indicate that the L393V variant does not seem to synergize in augmenting signaling of the acquired V617F variant (PMID: 27647865); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23670291, 33792220, 20417861, 31676277, 34426522, 27647865, 22762550, 34958119, 35304527, 37834019, 37762110, 38468832) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PhyloP100		2.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.070	.;N
REVEL	Benign	0.091
Sift	Benign	0.76	.;T
Sift4G	Benign	0.87	.;T
Polyphen		0.25	.;B
Vest4		0.70
MVP		0.56
MPC		0.20
ClinPred		0.0097	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.33
Mutation Taster		=72/28	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: rs2230723; hg19: chr9-5065003;