rs2227306

Positions:

• chr4-73741338-C-T

Variant summary

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

The NM_000584.4(CXCL8):​c.65-204C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,034 control chromosomes in the GnomAD database, including 8,700 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 0.32 (8700 hom., cov: 32)
• Consequence: CXCL8 NM_000584.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46

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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCL8	NM_000584.4	c.65-204C>T		intron_variant		ENST00000307407.8	NP_000575.1
CXCL8	NM_001354840.3	c.65-204C>T		intron_variant			NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8	c.65-204C>T		intron_variant		1	NM_000584.4	ENSP00000306512	P1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47926 AN: 151916 Hom.: 8704 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.338

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47926 AN: 152034 Hom.: 8700 Cov.: 32 AF XY: 0.310 AC XY: 23047 AN XY: 74314

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.420

Gnomad4 OTH AF: 0.340

Alfa AF: 0.362 Hom.: 1685

Bravo AF: 0.306

Asia WGS AF: 0.276 AC: 961 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.45
DANN	Benign	0.37

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: rs2227306; hg19: chr4-74607055;