rs2256298

Variant names:

• chr1-64864999-G-A
• rs2256298
• NM_002227.4:c.991-27C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-64864999-G-A
• chr1-64864999-G-C

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.991-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,571,840 control chromosomes in the GnomAD database, including 61,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10916 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50120 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.181
• Publications: 22 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=-0.83).
• BP6: Variant 1-64864999-G-A is Benign according to our data. Variant chr1-64864999-G-A is described in ClinVar as Benign. ClinVar VariationId is 2628145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.991-27C>T		intron_variant	Intron 7 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.991-27C>T		intron_variant	Intron 7 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53296 AN: 151904 Hom.: 10874 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.327

GnomAD2 exomes AF: 0.303 AC: 72948 AN: 240654 AF XY: 0.290

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.333

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.257 AC: 364462 AN: 1419818 Hom.: 50120 Cov.: 25 AF XY: 0.255 AC XY: 180475 AN XY: 707950

African (AFR) AF: 0.587 AC: 18879 AN: 32172

American (AMR) AF: 0.460 AC: 19708 AN: 42810

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7874 AN: 25582

East Asian (EAS) AF: 0.303 AC: 11970 AN: 39484

South Asian (SAS) AF: 0.235 AC: 19674 AN: 83608

European-Finnish (FIN) AF: 0.237 AC: 12458 AN: 52658

Middle Eastern (MID) AF: 0.252 AC: 1107 AN: 4394

European-Non Finnish (NFE) AF: 0.238 AC: 256980 AN: 1080288

Other (OTH) AF: 0.269 AC: 15812 AN: 58822

GnomAD4 genome AF: 0.351 AC: 53400 AN: 152022 Hom.: 10916 Cov.: 32 AF XY: 0.351 AC XY: 26056 AN XY: 74312

African (AFR) AF: 0.571 AC: 23648 AN: 41428

American (AMR) AF: 0.402 AC: 6148 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3468

East Asian (EAS) AF: 0.306 AC: 1579 AN: 5166

South Asian (SAS) AF: 0.227 AC: 1093 AN: 4820

European-Finnish (FIN) AF: 0.239 AC: 2521 AN: 10564

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.241 AC: 16359 AN: 67976

Other (OTH) AF: 0.334 AC: 706 AN: 2116

Alfa AF: 0.279 Hom.: 11197

Bravo AF: 0.375

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2256298; hg19: chr1-65330682; COSMIC: COSV61087701; COSMIC: COSV61087701;