dbSNP rs2230588: JAK1:p.Pro733Pro (chr1-64844806-T-C) – ACMG Classification: Benign (-21 pts)

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

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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

JAK1 links:

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 ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK1	NM_002227.4	MANE Select	c.2199A>G	p.Pro733Pro	synonymous	Exon 16 of 25	NP_002218.2	P23458
JAK1	NM_001320923.2		c.2199A>G	p.Pro733Pro	synonymous	Exon 17 of 26	NP_001307852.1	P23458
JAK1	NM_001321852.2		c.2199A>G	p.Pro733Pro	synonymous	Exon 16 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK1	ENST00000342505.5	TSL:5 MANE Select	c.2199A>G	p.Pro733Pro	synonymous	Exon 16 of 25	ENSP00000343204.4	P23458
JAK1	ENST00000671929.2		c.2199A>G	p.Pro733Pro	synonymous	Exon 17 of 26	ENSP00000500485.1	P23458
JAK1	ENST00000671954.2		c.2199A>G	p.Pro733Pro	synonymous	Exon 17 of 26	ENSP00000500841.1	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

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.:

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

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

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.:

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:

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

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

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.014

(source)

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)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over