GeneBe

NM_004972.4:c.1177C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004972.4(JAK2):ā€‹c.1177C>Gā€‹(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: š‘“ 0.013 ( 25 hom., cov: 33)
Exomes š‘“: 0.0058 ( 58 hom. )

Consequence

JAK2
NM_004972.4 missense

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 2.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 134563.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2, not_provided=1}.
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1967 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAK2NM_004972.4 linkc.1177C>G p.Leu393Val missense_variant Exon 9 of 25 ENST00000381652.4 NP_004963.1 O60674

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAK2ENST00000381652.4 linkc.1177C>G p.Leu393Val missense_variant Exon 9 of 25 1 NM_004972.4 ENSP00000371067.4 O60674
JAK2ENST00000636127.1 linkc.1177C>G p.Leu393Val missense_variant Exon 9 of 16 5 ENSP00000489812.1 A0A1B0GTR9

Frequencies

GnomAD3 genomes
AF:
0.0129
AC:
1967
AN:
152122
Hom.:
25
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.00766
AC:
1877
AN:
245174
Hom.:
16
AF XY:
0.00714
AC XY:
946
AN XY:
132546
show subpopulations
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 SAS exome
AF:
0.000378
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0219
Gnomad4 AMR exome
AF:
0.0150
Gnomad4 ASJ exome
AF:
0.0355
Gnomad4 EAS exome
AF:
0.0000508
Gnomad4 SAS exome
AF:
0.000426
Gnomad4 FIN exome
AF:
0.000263
Gnomad4 NFE exome
AF:
0.00476
Gnomad4 OTH exome
AF:
0.0117
GnomAD4 genome
AF:
0.0129
AC:
1967
AN:
152240
Hom.:
25
Cov.:
33
AF XY:
0.0130
AC XY:
964
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0263
Gnomad4 AMR
AF:
0.0253
Gnomad4 ASJ
AF:
0.0340
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00471
Gnomad4 OTH
AF:
0.0156
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:2Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:3
Jul 11, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BP4 -

Jul 11, 2024
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); Identified in samples from diffuse large B-cell tumors, BCR-ABL1 negative and JAK2V617F 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 indicates 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) -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

JAK2: BS1, BS2 -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely 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
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2230723; hg19: chr9-5065003; COSMIC: COSV104431585; API