dbSNP rs2227538: CXCL8:c.-1C>T (chr4-73740658-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.447

Publications

13 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL8	NM_000584.4 link	c.-1C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000307407.8	NP_000575.1	P10145A0A024RDA5
CXCL8	NM_001354840.3 link	c.-1C>T		5_prime_UTR_variant	Exon 1 of 3		NP_001341769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL8	ENST00000307407.8 link	c.-1C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_000584.4	ENSP00000306512.3		P10145

Frequencies

GnomAD3 genomes

AF:

0.0610

AC:

9281

AN:

152150

Hom.:

971

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00562

AC XY:

4088

AN XY:

726958

show subpopulations

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:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000603

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000402

AC:

447

AN:

1111626

Other (OTH)

AF:

0.0151

AC:

914

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

321

643

964

1286

1607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0610

AC:

9292

AN:

152268

Hom.:

967

Cov.:

AF XY:

0.0595

AC XY:

4428

AN XY:

74452

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00186

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68016

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

374

748

1121

1495

1869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0236

Hom.:

1155

Bravo

AF:

0.0693

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000892

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.45

PromoterAI

-0.16

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over