Variant rs2230588 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.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

Clinical Significance

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

Conservation

PhyloP100: -2.98

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:

JAK1 (HGNC:):

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=-0.91).

BP6

Variant 1-64844806-T-C is Benign according to our data. Variant chr1-64844806-T-C is described in ClinVar 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/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.2199A>G	p.Pro733Pro	synonymous_variant	16/25	ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 linkuse as main transcript	c.2199A>G	p.Pro733Pro	synonymous_variant	16/25	5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54388

AN:

151970

Hom.:

11771

Cov.:

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

GnomAD3 exomes

AF:

0.295

AC:

73644

AN:

249524

Hom.:

12159

AF XY:

0.285

AC XY:

38524

AN XY:

135372

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 SAS exome

AF:

0.236

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.:

AF XY:

0.251

AC XY:

182470

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.628

Gnomad4 AMR exome

AF:

0.349

Gnomad4 ASJ exome

AF:

0.353

Gnomad4 EAS exome

AF:

0.296

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.276

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.273

GnomAD4 genome

AF:

0.358

AC:

54492

AN:

152088

Hom.:

11817

Cov.:

AF XY:

0.356

AC XY:

26477

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.615

Gnomad4 AMR

AF:

0.307

Gnomad4 ASJ

AF:

0.357

Gnomad4 EAS

AF:

0.295

Gnomad4 SAS

AF:

0.229

Gnomad4 FIN

AF:

0.287

Gnomad4 NFE

AF:

0.242

Gnomad4 OTH

AF:

0.346

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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