chr1-64844806-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002227.4(JAK1):​c.2199A>G​(p.Pro733Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,788 control chromosomes in the GnomAD database, including 62,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 11817 hom., cov: 33)
Exomes 𝑓: 0.25 ( 50240 hom. )

Consequence

JAK1
NM_002227.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.98

Publications

29 publications found
Variant links:
Genes affected
JAK1 (HGNC:6190): (Janus kinase 1) This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]
JAK1 Gene-Disease associations (from GenCC):
  • autoinflammation, immune dysregulation, and eosinophilia
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
Variant 1-64844806-T-C is Benign according to our data. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-64844806-T-C is described in CliVar as Benign. Clinvar id is 1169782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.98 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAK1NM_002227.4 linkc.2199A>G p.Pro733Pro synonymous_variant Exon 16 of 25 ENST00000342505.5 NP_002218.2 P23458

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAK1ENST00000342505.5 linkc.2199A>G p.Pro733Pro synonymous_variant Exon 16 of 25 5 NM_002227.4 ENSP00000343204.4 P23458

Frequencies

GnomAD3 genomes
AF:
0.358
AC:
54388
AN:
151970
Hom.:
11771
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.614
Gnomad AMI
AF:
0.170
Gnomad AMR
AF:
0.307
Gnomad ASJ
AF:
0.357
Gnomad EAS
AF:
0.296
Gnomad SAS
AF:
0.228
Gnomad FIN
AF:
0.287
Gnomad MID
AF:
0.244
Gnomad NFE
AF:
0.242
Gnomad OTH
AF:
0.339
GnomAD2 exomes
AF:
0.295
AC:
73644
AN:
249524
AF XY:
0.285
show subpopulations
Gnomad AFR exome
AF:
0.621
Gnomad AMR exome
AF:
0.352
Gnomad ASJ exome
AF:
0.356
Gnomad EAS exome
AF:
0.319
Gnomad FIN exome
AF:
0.287
Gnomad NFE exome
AF:
0.242
Gnomad OTH exome
AF:
0.291
GnomAD4 exome
AF:
0.252
AC:
368756
AN:
1461700
Hom.:
50240
Cov.:
36
AF XY:
0.251
AC XY:
182470
AN XY:
727156
show subpopulations
African (AFR)
AF:
0.628
AC:
21017
AN:
33476
American (AMR)
AF:
0.349
AC:
15600
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.353
AC:
9228
AN:
26134
East Asian (EAS)
AF:
0.296
AC:
11738
AN:
39700
South Asian (SAS)
AF:
0.231
AC:
19919
AN:
86248
European-Finnish (FIN)
AF:
0.276
AC:
14746
AN:
53418
Middle Eastern (MID)
AF:
0.267
AC:
1537
AN:
5764
European-Non Finnish (NFE)
AF:
0.233
AC:
258509
AN:
1111850
Other (OTH)
AF:
0.273
AC:
16462
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
15522
31044
46566
62088
77610
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
8978
17956
26934
35912
44890
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.358
AC:
54492
AN:
152088
Hom.:
11817
Cov.:
33
AF XY:
0.356
AC XY:
26477
AN XY:
74326
show subpopulations
African (AFR)
AF:
0.615
AC:
25501
AN:
41470
American (AMR)
AF:
0.307
AC:
4700
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.357
AC:
1241
AN:
3472
East Asian (EAS)
AF:
0.295
AC:
1519
AN:
5152
South Asian (SAS)
AF:
0.229
AC:
1102
AN:
4818
European-Finnish (FIN)
AF:
0.287
AC:
3031
AN:
10578
Middle Eastern (MID)
AF:
0.235
AC:
69
AN:
294
European-Non Finnish (NFE)
AF:
0.242
AC:
16445
AN:
67992
Other (OTH)
AF:
0.346
AC:
729
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
1627
3254
4880
6507
8134
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
500
1000
1500
2000
2500
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.300
Hom.:
4081
Bravo
AF:
0.374
Asia WGS
AF:
0.311
AC:
1081
AN:
3478
EpiCase
AF:
0.248
EpiControl
AF:
0.243

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
Nov 12, 2023
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
CADD
Benign
0.014
DANN
Benign
0.32
PhyloP100
-3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Mutation Taster
=98/2
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230588; hg19: chr1-65310489; COSMIC: COSV61087119; COSMIC: COSV61087119; API