rs2227549

Positions:

• chr4-73741020-A-C
• chr4-73741020-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000584.4(CXCL8):​c.64+298A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 152,266 control chromosomes in the GnomAD database, including 5 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 0.0023 (5 hom., cov: 32)
• Consequence: CXCL8 NM_000584.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890

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]

CXCL8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAd4 at 350 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCL8	NM_000584.4	c.64+298A>C		intron_variant		ENST00000307407.8	NP_000575.1
CXCL8	NM_001354840.3	c.64+298A>C		intron_variant			NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8	c.64+298A>C		intron_variant		1	NM_000584.4	ENSP00000306512.3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152148 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00431

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

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152266 Hom.: 5 Cov.: 32 AF XY: 0.00210 AC XY: 156 AN XY: 74438

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.0000882 Hom.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.65
DANN	Benign	0.36

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: rs2227549; hg19: chr4-74606737;