rs4674259

Positions:

• chr2-218126282-G-A
• chr2-218126282-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000453237.5(CXCR2):​c.-140-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,100 control chromosomes in the GnomAD database, including 28,440 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 0.60 (28405 hom., cov: 31)
  • Exomes 𝑓: 0.59 (35 hom.)
• Consequence: CXCR2 ENST00000453237.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001066
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185

Genes affected

CXCR2 (HGNC:6027): (C-X-C motif chemokine receptor 2) The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein activated second messenger system. This receptor also binds to chemokine (C-X-C motif) ligand 1 (CXCL1/MGSA), a protein with melanoma growth stimulating activity, and has been shown to be a major component required for serum-dependent melanoma cell growth. This receptor mediates neutrophil migration to sites of inflammation. The angiogenic effects of IL8 in intestinal microvascular endothelial cells are found to be mediated by this receptor. Knockout studies in mice suggested that this receptor controls the positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. This gene, IL8RA, a gene encoding another high affinity IL8 receptor, as well as IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36. Alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR2	NM_001557.4	c.-149G>A		5_prime_UTR_variant	1/3	ENST00000318507.7	NP_001548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR2	ENST00000318507.7	c.-149G>A		5_prime_UTR_variant	1/3	1	NM_001557.4	ENSP00000319635	P1

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90725 AN: 151772 Hom.: 28372 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.622

GnomAD4 exome AF: 0.590 AC: 124 AN: 210 Hom.: 35 Cov.: 0 AF XY: 0.636 AC XY: 75 AN XY: 118

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.598 AC: 90796 AN: 151890 Hom.: 28405 Cov.: 31 AF XY: 0.593 AC XY: 44021 AN XY: 74236

Gnomad4 AFR AF: 0.782

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.653

Gnomad4 EAS AF: 0.360

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.621

Alfa AF: 0.554 Hom.: 31498

Bravo AF: 0.612

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.010		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: rs4674259; hg19: chr2-218991005;