rs12129819

Variant names:

• chr1-64837976-C-T
• rs12129819
• NM_002227.4:c.3096G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002227.4(JAK1):​c.3096G>A​(p.Lys1032Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,613,920 control chromosomes in the GnomAD database, including 7,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (566 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7028 hom.)
• Consequence: JAK1 NM_002227.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53
• Publications: 17 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 1-64837976-C-T is Benign according to our data. Variant chr1-64837976-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.3096G>A	p.Lys1032Lys	synonymous	Exon 22 of 25	NP_002218.2	P23458
	JAK1	NM_001320923.2		c.3096G>A	p.Lys1032Lys	synonymous	Exon 23 of 26	NP_001307852.1	P23458
	JAK1	NM_001321852.2		c.3096G>A	p.Lys1032Lys	synonymous	Exon 22 of 25	NP_001308781.1	P23458

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.3096G>A	p.Lys1032Lys	synonymous	Exon 22 of 25	ENSP00000343204.4	P23458
	JAK1	ENST00000671929.2		c.3096G>A	p.Lys1032Lys	synonymous	Exon 23 of 26	ENSP00000500485.1	P23458
	JAK1	ENST00000671954.2		c.3096G>A	p.Lys1032Lys	synonymous	Exon 23 of 26	ENSP00000500841.1	P23458

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11601 AN: 152116 Hom.: 566 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0796

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0871

GnomAD2 exomes AF: 0.0766 AC: 19123 AN: 249512 AF XY: 0.0757

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0967

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0916 AC: 133865 AN: 1461686 Hom.: 7028 Cov.: 32 AF XY: 0.0900 AC XY: 65441 AN XY: 727146

African (AFR) AF: 0.0323 AC: 1081 AN: 33480

American (AMR) AF: 0.0572 AC: 2557 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 2457 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0146 AC: 1256 AN: 86256

European-Finnish (FIN) AF: 0.112 AC: 5987 AN: 53420

Middle Eastern (MID) AF: 0.0829 AC: 478 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115101 AN: 1111822

Other (OTH) AF: 0.0819 AC: 4945 AN: 60388

GnomAD4 genome AF: 0.0761 AC: 11592 AN: 152234 Hom.: 566 Cov.: 32 AF XY: 0.0759 AC XY: 5650 AN XY: 74446

African (AFR) AF: 0.0340 AC: 1414 AN: 41536

American (AMR) AF: 0.0794 AC: 1213 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 324 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4828

European-Finnish (FIN) AF: 0.113 AC: 1201 AN: 10598

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7072 AN: 68020

Other (OTH) AF: 0.0862 AC: 182 AN: 2112

Alfa AF: 0.0934 Hom.: 612

Bravo AF: 0.0742

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	7.8
DANN	Benign	0.87
PhyloP100		1.5
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs12129819; hg19: chr1-65303659; COSMIC: COSV53805030; COSMIC: COSV53805030;