rs2254002

Variant names:

• chr1-64835986-C-A
• rs2254002
• NM_002227.4:c.3258+112G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-64835986-C-A
• chr1-64835986-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002227.4(JAK1):​c.3258+112G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 675,290 control chromosomes in the GnomAD database, including 68,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (23604 hom., cov: 32)
  • Exomes 𝑓: 0.40 (45151 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.845
• Publications: 6 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: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-64835986-C-A is Benign according to our data. Variant chr1-64835986-C-A is described in ClinVar as Benign. ClinVar VariationId is 2688493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.3258+112G>T		intron	N/A	NP_002218.2
	JAK1	NM_001320923.2		c.3258+112G>T		intron	N/A	NP_001307852.1
	JAK1	NM_001321852.2		c.3258+112G>T		intron	N/A	NP_001308781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.3258+112G>T		intron	N/A	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.3258+112G>T		intron	N/A	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.3258+112G>T		intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78104 AN: 151734 Hom.: 23546 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.401 AC: 210097 AN: 523438 Hom.: 45151 AF XY: 0.395 AC XY: 110086 AN XY: 278370

African (AFR) AF: 0.841 AC: 11056 AN: 13152

American (AMR) AF: 0.513 AC: 13310 AN: 25934

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 7089 AN: 15092

East Asian (EAS) AF: 0.594 AC: 19450 AN: 32750

South Asian (SAS) AF: 0.359 AC: 17375 AN: 48414

European-Finnish (FIN) AF: 0.404 AC: 19806 AN: 48998

Middle Eastern (MID) AF: 0.379 AC: 1384 AN: 3652

European-Non Finnish (NFE) AF: 0.353 AC: 108393 AN: 307006

Other (OTH) AF: 0.430 AC: 12234 AN: 28440

GnomAD4 genome AF: 0.515 AC: 78227 AN: 151852 Hom.: 23604 Cov.: 32 AF XY: 0.515 AC XY: 38174 AN XY: 74168

African (AFR) AF: 0.840 AC: 34797 AN: 41422

American (AMR) AF: 0.470 AC: 7169 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1670 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3156 AN: 5154

South Asian (SAS) AF: 0.356 AC: 1710 AN: 4808

European-Finnish (FIN) AF: 0.420 AC: 4395 AN: 10474

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23870 AN: 67952

Other (OTH) AF: 0.489 AC: 1031 AN: 2110

Alfa AF: 0.484 Hom.: 2642

Bravo AF: 0.538

Asia WGS AF: 0.525 AC: 1824 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		-0.84
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: rs2254002; hg19: chr1-65301669; COSMIC: COSV53810753; COSMIC: COSV53810753;