rs2227543

Variant names:

• chr4-73742193-C-T
• rs2227543
• ENST00000401931.1:c.*157C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354840.3(CXCL8):​c.*157C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 590,280 control chromosomes in the GnomAD database, including 43,050 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 (8953 hom., cov: 31)
  • Exomes 𝑓: 0.39 (34097 hom.)
• Consequence: CXCL8 NM_001354840.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.448

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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL8	NM_000584.4	c.284+161C>T		intron_variant	Intron 3 of 3	ENST00000307407.8	NP_000575.1
CXCL8	NM_001354840.3	c.*157C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8	c.284+161C>T		intron_variant	Intron 3 of 3	1	NM_000584.4	ENSP00000306512.3

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48639 AN: 151618 Hom.: 8956 Cov.: 31

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.389 AC: 170568 AN: 438542 Hom.: 34097 Cov.: 5 AF XY: 0.387 AC XY: 90070 AN XY: 232562

Gnomad4 AFR exome AF: 0.133 AC: 1490 AN: 11234

Gnomad4 AMR exome AF: 0.294 AC: 4325 AN: 14710

Gnomad4 ASJ exome AF: 0.357 AC: 4653 AN: 13040

Gnomad4 EAS exome AF: 0.325 AC: 9567 AN: 29452

Gnomad4 SAS exome AF: 0.342 AC: 12537 AN: 36618

Gnomad4 FIN exome AF: 0.379 AC: 15643 AN: 41314

Gnomad4 NFE exome AF: 0.423 AC: 112217 AN: 265376

Gnomad4 Remaining exome AF: 0.379 AC: 9436 AN: 24876

GnomAD4 genome AF: 0.321 AC: 48641 AN: 151738 Hom.: 8953 Cov.: 31 AF XY: 0.317 AC XY: 23463 AN XY: 74098

Gnomad4 AFR AF: 0.133 AC: 0.133211 AN: 0.133211

Gnomad4 AMR AF: 0.299 AC: 0.298937 AN: 0.298937

Gnomad4 ASJ AF: 0.351 AC: 0.350634 AN: 0.350634

Gnomad4 EAS AF: 0.370 AC: 0.370097 AN: 0.370097

Gnomad4 SAS AF: 0.355 AC: 0.354799 AN: 0.354799

Gnomad4 FIN AF: 0.373 AC: 0.373425 AN: 0.373425

Gnomad4 NFE AF: 0.422 AC: 0.421996 AN: 0.421996

Gnomad4 OTH AF: 0.342 AC: 0.34188 AN: 0.34188

Alfa AF: 0.381 Hom.: 15395

Bravo AF: 0.309

Asia WGS AF: 0.331 AC: 1149 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.44
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

Publications

LitVar

Other links and lift over

dbSNP: rs2227543; hg19: chr4-74607910;