2-218126282-G-A

Variant names:

• chr2-218126282-G-A
• rs4674259
• NM_001557.4:c.-149G>A

Variant summary

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

The NM_001557.4(CXCR2):​c.-149G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,100 control chromosomes in the GnomAD database, including 28,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.60 (28405 hom., cov: 31)
  • Exomes 𝑓: 0.59 (35 hom.)
• Consequence: CXCR2 NM_001557.4 5_prime_UTR
• Scores: Splicing: ADA: 0.0001066
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 38 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 = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001557.4. 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
	CXCR2	NM_001557.4	MANE Select	c.-149G>A		5_prime_UTR	Exon 1 of 3	NP_001548.1
	CXCR2	NM_001168298.2		c.-140-9G>A		intron	N/A	NP_001161770.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	ENST00000318507.7	TSL:1 MANE Select	c.-149G>A		5_prime_UTR	Exon 1 of 3	ENSP00000319635.2
	CXCR2	ENST00000453237.5	TSL:1	c.-140-9G>A		intron	N/A	ENSP00000413686.1
	CXCR2	ENST00000454148.1	TSL:1	c.-140-9G>A		intron	N/A	ENSP00000415148.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.610 AC: 83 AN: 136

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.625 AC: 35 AN: 56

Other (OTH) AF: 0.500 AC: 2 AN: 4

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

African (AFR) AF: 0.782 AC: 32441 AN: 41466

American (AMR) AF: 0.564 AC: 8604 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2267 AN: 3472

East Asian (EAS) AF: 0.360 AC: 1853 AN: 5152

South Asian (SAS) AF: 0.589 AC: 2832 AN: 4808

European-Finnish (FIN) AF: 0.432 AC: 4547 AN: 10520

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 36067 AN: 67896

Other (OTH) AF: 0.621 AC: 1309 AN: 2108

Alfa AF: 0.556 Hom.: 47091

Bravo AF: 0.612

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.69
PhyloP100		0.18
PromoterAI		-0.11	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4674259; hg19: chr2-218991005;