2-218125582-GTTT-GTT

Variant names:

• chr2-218125582-GT-G
• rs35231134
• ENST00000453237.5:c.-141+224delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000453237.5(CXCR2):​c.-141+224delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 148,136 control chromosomes in the GnomAD database, including 24,659 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (24657 hom., cov: 0)
  • Exomes 𝑓: 0.42 (2 hom.)
• Consequence: CXCR2 ENST00000453237.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.557
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453237.5. 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.-141+234delT		intron	N/A	NP_001161770.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	ENST00000453237.5	TSL:1	c.-141+224delT		intron	N/A	ENSP00000413686.1
	CXCR2	ENST00000449014.5	TSL:1	c.-339delT		upstream_gene	N/A	ENSP00000410506.1
	CXCR2	ENST00000415392.5	TSL:5	c.-268delT		upstream_gene	N/A	ENSP00000392348.1

Frequencies

GnomAD3 genomes AF: 0.569 AC: 84275 AN: 148012 Hom.: 24646 Cov.: 0

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.588

GnomAD4 exome AF: 0.417 AC: 10 AN: 24 Hom.: 2 AF XY: 0.438 AC XY: 7 AN XY: 16

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.438 AC: 7 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 3 AN: 6

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.569 AC: 84324 AN: 148112 Hom.: 24657 Cov.: 0 AF XY: 0.565 AC XY: 40787 AN XY: 72144

African (AFR) AF: 0.746 AC: 30165 AN: 40410

American (AMR) AF: 0.533 AC: 7930 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2098 AN: 3418

East Asian (EAS) AF: 0.329 AC: 1641 AN: 4992

South Asian (SAS) AF: 0.545 AC: 2538 AN: 4658

European-Finnish (FIN) AF: 0.437 AC: 4289 AN: 9818

Middle Eastern (MID) AF: 0.668 AC: 191 AN: 286

European-Non Finnish (NFE) AF: 0.505 AC: 33687 AN: 66736

Other (OTH) AF: 0.586 AC: 1194 AN: 2036

Alfa AF: 0.133 Hom.: 521

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

Splicing

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

Other links and lift over

dbSNP: rs35231134; hg19: chr2-218990305;