Variant rs2230587 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002227.4(JAK1):c.2049C>T(p.Ser683=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,782 control chromosomes in the GnomAD database, including 15,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1853 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13254 hom. )

Consequence

JAK1
NM_002227.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.92

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 1-64845579-G-A is Benign according to our data. Variant chr1-64845579-G-A is described in ClinVar as [Benign]. Clinvar id is 1169783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.2049C>T	p.Ser683=	synonymous_variant	15/25	ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5 linkuse as main transcript	c.2049C>T	p.Ser683=	synonymous_variant	15/25	5	NM_002227.4	A1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22992

AN:

151954

Hom.:

1850

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.150

AC:

37484

AN:

249582

Hom.:

3241

AF XY:

0.146

AC XY:

19832

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.203

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.316

Gnomad SAS exome

AF:

0.158

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.129

AC:

189012

AN:

1461710

Hom.:

13254

Cov.:

AF XY:

0.130

AC XY:

94197

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.199

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.131

Gnomad4 EAS exome

AF:

0.295

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.146

GnomAD4 genome

AF:

0.151

AC:

23015

AN:

152072

Hom.:

1853

Cov.:

AF XY:

0.154

AC XY:

11415

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.197

Gnomad4 AMR

AF:

0.156

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.314

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.140

Alfa

AF:

0.130

Hom.:

968

Bravo

AF:

0.157

Asia WGS

AF:

0.231

AC:

800

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

JAK1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.52

DANN

Benign

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over