rs2227538

Positions:

• chr4-73740658-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000307407.8(CXCL8):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,488 control chromosomes in the GnomAD database, including 1,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.061 (967 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (876 hom.)
• Consequence: CXCL8 ENST00000307407.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447

Genes affected

CXCL8 (HGNC:6025): (C-X-C motif chemokine ligand 8) The protein encoded by this gene is a member of the CXC chemokine family and is a major mediator of the inflammatory response. The encoded protein is commonly referred to as interleukin-8 (IL-8). IL-8 is secreted by mononuclear macrophages, neutrophils, eosinophils, T lymphocytes, epithelial cells, and fibroblasts. It functions as a chemotactic factor by guiding the neutrophils to the site of infection. Bacterial and viral products rapidly induce IL-8 expression. IL-8 also participates with other cytokines in the proinflammatory signaling cascade and plays a role in systemic inflammatory response syndrome (SIRS). This gene is believed to play a role in the pathogenesis of the lower respiratory tract infection bronchiolitis, a common respiratory tract disease caused by the respiratory syncytial virus (RSV). The overproduction of this proinflammatory protein is thought to cause the lung inflammation associated with csytic fibrosis. This proinflammatory protein is also suspected of playing a role in coronary artery disease and endothelial dysfunction. This protein is also secreted by tumor cells and promotes tumor migration, invasion, angiogenesis and metastasis. This chemokine is also a potent angiogenic factor. The binding of IL-8 to one of its receptors (IL-8RB/CXCR2) increases the permeability of blood vessels and increasing levels of IL-8 are positively correlated with increased severity of multiple disease outcomes (eg, sepsis). This gene and other members of the CXC chemokine gene family form a gene cluster in a region of chromosome 4q. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCL8	NM_000584.4	c.-1C>T		5_prime_UTR_variant	1/4	ENST00000307407.8	NP_000575.1
CXCL8	NM_001354840.3	c.-1C>T		5_prime_UTR_variant	1/3		NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8	c.-1C>T		5_prime_UTR_variant	1/4	1	NM_000584.4	ENSP00000306512	P1

Frequencies

GnomAD3 genomes AF: 0.0610 AC: 9281 AN: 152150 Hom.: 971 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0156 AC: 3916 AN: 250936 Hom.: 394 AF XY: 0.0116 AC XY: 1573 AN XY: 135622

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000740

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.00635 AC: 9280 AN: 1461220 Hom.: 876 Cov.: 30 AF XY: 0.00562 AC XY: 4088 AN XY: 726958

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0610 AC: 9292 AN: 152268 Hom.: 967 Cov.: 32 AF XY: 0.0595 AC XY: 4428 AN XY: 74452

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0117 Hom.: 330

Bravo AF: 0.0693

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000892

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.91

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

LitVar

Other links and lift over

dbSNP: rs2227538; hg19: chr4-74606375;