2-218135587-C-G

Variant names:

• chr2-218135587-C-G
• NM_001557.4:c.786C>G
• CXCR2 p.Leu262Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001557.4(CXCR2):​c.786C>G​(p.Leu262Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L262L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CXCR2 NM_001557.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.953
• 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

ENSG00000305582 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=0.953 with no splicing effect.

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.786C>G	p.Leu262Leu	synonymous	Exon 3 of 3	NP_001548.1	P25025
	CXCR2	NM_001168298.2		c.786C>G	p.Leu262Leu	synonymous	Exon 4 of 4	NP_001161770.1	P25025

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	ENST00000318507.7	TSL:1 MANE Select	c.786C>G	p.Leu262Leu	synonymous	Exon 3 of 3	ENSP00000319635.2	P25025
	CXCR2	ENST00000875238.1		c.786C>G	p.Leu262Leu	synonymous	Exon 3 of 3	ENSP00000545297.1
	CXCR2	ENST00000875239.1		c.786C>G	p.Leu262Leu	synonymous	Exon 3 of 3	ENSP00000545298.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 95

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-219000310;