rs2227538

Variant names:

• chr4-73740658-C-T
• rs2227538
• NM_000584.4:c.-1C>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.-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 NM_000584.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447
• Publications: 13 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=-0.51).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	NM_000584.4	MANE Select	c.-1C>T		5_prime_UTR	Exon 1 of 4	NP_000575.1
	CXCL8	NM_001354840.3		c.-1C>T		5_prime_UTR	Exon 1 of 3	NP_001341769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL8	ENST00000307407.8	TSL:1 MANE Select	c.-1C>T		5_prime_UTR	Exon 1 of 4	ENSP00000306512.3
	CXCL8	ENST00000401931.2	TSL:1	c.-1C>T		5_prime_UTR	Exon 1 of 3	ENSP00000385908.1
	CXCL8	ENST00000483500.1	TSL:2	n.90C>T		non_coding_transcript_exon	Exon 1 of 2

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

GnomAD2 exomes AF: 0.0156 AC: 3916 AN: 250936 AF XY: 0.0116

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 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

African (AFR) AF: 0.216 AC: 7224 AN: 33372

American (AMR) AF: 0.0117 AC: 525 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5764

European-Non Finnish (NFE) AF: 0.000402 AC: 447 AN: 1111626

Other (OTH) AF: 0.0151 AC: 914 AN: 60362

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

African (AFR) AF: 0.212 AC: 8811 AN: 41518

American (AMR) AF: 0.0198 AC: 303 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68016

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0236 Hom.: 1155

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		0.45
PromoterAI		-0.16	Neutral
Mutation Taster		=300/0	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: rs2227538; hg19: chr4-74606375;