chr2-218125863-C-T

Variant names:

• chr2-218125863-C-T
• rs4674258
• ENST00000453237.5:c.-140-428C>T

Variant summary

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

The NM_001168298.2(CXCR2):​c.-140-428C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,340 control chromosomes in the GnomAD database, including 19,169 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 0.50 (19101 hom., cov: 29)
  • Exomes 𝑓: 0.44 (68 hom.)
• Consequence: CXCR2 NM_001168298.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.496
• Publications: 15 publications found

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]

CXCR2 Gene-Disease associations (from GenCC):

• WHIM syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive severe congenital neutropenia due to CXCR2 deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168298.2. 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
	CXCR2	NM_001168298.2		c.-140-428C>T		intron	N/A	NP_001161770.1
	CXCR2	NM_001557.4	MANE Select	c.-568C>T		upstream_gene	N/A	NP_001548.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	ENST00000453237.5	TSL:1	c.-140-428C>T		intron	N/A	ENSP00000413686.1
	CXCR2	ENST00000449014.5	TSL:1	c.-141+82C>T		intron	N/A	ENSP00000410506.1
	CXCR2	ENST00000875240.1		c.-516C>T		5_prime_UTR	Exon 1 of 2	ENSP00000545299.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75493 AN: 151614 Hom.: 19080 Cov.: 29

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.442 AC: 269 AN: 608 Hom.: 68 Cov.: 0 AF XY: 0.454 AC XY: 168 AN XY: 370

African (AFR) AF: 0.500 AC: 4 AN: 8

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.188 AC: 6 AN: 32

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 0.350 AC: 89 AN: 254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.540 AC: 150 AN: 278

Other (OTH) AF: 0.583 AC: 14 AN: 24

GnomAD4 genome AF: 0.498 AC: 75533 AN: 151732 Hom.: 19101 Cov.: 29 AF XY: 0.493 AC XY: 36581 AN XY: 74170

African (AFR) AF: 0.543 AC: 22470 AN: 41356

American (AMR) AF: 0.507 AC: 7725 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1989 AN: 3464

East Asian (EAS) AF: 0.327 AC: 1687 AN: 5152

South Asian (SAS) AF: 0.494 AC: 2372 AN: 4802

European-Finnish (FIN) AF: 0.399 AC: 4197 AN: 10532

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33146 AN: 67886

Other (OTH) AF: 0.532 AC: 1120 AN: 2104

Alfa AF: 0.495 Hom.: 6961

Bravo AF: 0.506

Asia WGS AF: 0.392 AC: 1365 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.9
DANN	Benign	0.76
PhyloP100		0.50
PromoterAI		-0.0014	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4674258; hg19: chr2-218990586;