Genetic Variant NM_002227.4:c.2049C>T (chr1-64845579-G-A) – 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.2049C>T(p.Ser683Ser) 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:4

Conservation

PhyloP100: -1.92

Publications

33 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=-0.75).

BP6

Variant 1-64845579-G-A is Benign according to our data. Variant chr1-64845579-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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.2049C>T	p.Ser683Ser	synonymous	Exon 15 of 25	NP_002218.2	P23458
JAK1	NM_001320923.2		c.2049C>T	p.Ser683Ser	synonymous	Exon 16 of 26	NP_001307852.1	P23458
JAK1	NM_001321852.2		c.2049C>T	p.Ser683Ser	synonymous	Exon 15 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.2049C>T	p.Ser683Ser	synonymous	Exon 15 of 25	ENSP00000343204.4	P23458
JAK1	ENST00000671929.2		c.2049C>T	p.Ser683Ser	synonymous	Exon 16 of 26	ENSP00000500485.1	P23458
JAK1	ENST00000671954.2		c.2049C>T	p.Ser683Ser	synonymous	Exon 16 of 26	ENSP00000500841.1	P23458

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

GnomAD2 exomes

AF:

0.150

AC:

37484

AN:

249582

AF XY:

0.146

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 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

African (AFR)

AF:

0.199

AC:

6670

AN:

33470

American (AMR)

AF:

0.176

AC:

7892

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3435

AN:

26134

East Asian (EAS)

AF:

0.295

AC:

11723

AN:

39700

South Asian (SAS)

AF:

0.159

AC:

13706

AN:

86252

European-Finnish (FIN)

AF:

0.127

AC:

6763

AN:

53420

Middle Eastern (MID)

AF:

0.116

AC:

667

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

129319

AN:

1111850

Other (OTH)

AF:

0.146

AC:

8837

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8396

16791

25187

33582

41978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5004

10008

15012

20016

25020

<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:

0.151

AC:

23015

AN:

152072

Hom.:

1853

Cov.:

AF XY:

0.154

AC XY:

11415

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.197

AC:

8149

AN:

41454

American (AMR)

AF:

0.156

AC:

2387

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

467

AN:

3468

East Asian (EAS)

AF:

0.314

AC:

1621

AN:

5162

South Asian (SAS)

AF:

0.156

AC:

751

AN:

4816

European-Finnish (FIN)

AF:

0.130

AC:

1375

AN:

10596

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7764

AN:

67980

Other (OTH)

AF:

0.140

AC:

296

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1000

2001

3001

4002

5002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.131

Hom.:

1082

Bravo

AF:

0.157

Asia WGS

AF:

0.231

AC:

800

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.109

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

JAK1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.52

(source)

DANN

Benign

0.40

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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