NM_000584.4:c.65-204C>T

Variant names:

• chr4-73741338-C-T
• rs2227306
• NM_000584.4:c.65-204C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 192 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000584.4. 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
	CXCL8	NM_000584.4	MANE Select	c.65-204C>T		intron	N/A	NP_000575.1
	CXCL8	NM_001354840.3		c.65-204C>T		intron	N/A	NP_001341769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	ENST00000307407.8	TSL:1 MANE Select	c.65-204C>T		intron	N/A	ENSP00000306512.3
	CXCL8	ENST00000401931.2	TSL:1	c.65-204C>T		intron	N/A	ENSP00000385908.1
	CXCL8	ENST00000483500.1	TSL:2	n.155-204C>T		intron	N/A

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

African (AFR) AF: 0.133 AC: 5499 AN: 41482

American (AMR) AF: 0.297 AC: 4536 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1706 AN: 5168

South Asian (SAS) AF: 0.278 AC: 1337 AN: 4816

European-Finnish (FIN) AF: 0.373 AC: 3936 AN: 10566

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28527 AN: 67960

Other (OTH) AF: 0.340 AC: 716 AN: 2108

Alfa AF: 0.354 Hom.: 1691

Bravo AF: 0.306

Asia WGS AF: 0.276 AC: 961 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.45
DANN	Benign	0.37
PhyloP100		-2.5
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: rs2227306; hg19: chr4-74607055;