chr2-218135737-C-T

Variant names:

• chr2-218135737-C-T
• rs45606837
• NM_001557.4:c.936C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001557.4(CXCR2):​c.936C>T​(p.Leu312Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,158 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 31)
  • Exomes 𝑓: 0.013 (201 hom.)
• Consequence: CXCR2 NM_001557.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.595
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-218135737-C-T is Benign according to our data. Variant chr2-218135737-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.595 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0102 (1558/152270) while in subpopulation SAS AF = 0.0384 (185/4816). AF 95% confidence interval is 0.0339. There are 16 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	NM_001557.4	MANE Select	c.936C>T	p.Leu312Leu	synonymous	Exon 3 of 3	NP_001548.1
	CXCR2	NM_001168298.2		c.936C>T	p.Leu312Leu	synonymous	Exon 4 of 4	NP_001161770.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR2	ENST00000318507.7	TSL:1 MANE Select	c.936C>T	p.Leu312Leu	synonymous	Exon 3 of 3	ENSP00000319635.2
	ENSG00000305582	ENST00000811769.1		n.152+4153G>A		intron	N/A
	ENSG00000305582	ENST00000811770.1		n.208+4153G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1560 AN: 152152 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.0137 AC: 3434 AN: 251476 AF XY: 0.0156

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0126 AC: 18440 AN: 1461888 Hom.: 201 Cov.: 34 AF XY: 0.0135 AC XY: 9847 AN XY: 727246

African (AFR) AF: 0.00233 AC: 78 AN: 33480

American (AMR) AF: 0.00400 AC: 179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 396 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0337 AC: 2903 AN: 86258

European-Finnish (FIN) AF: 0.0188 AC: 1005 AN: 53420

Middle Eastern (MID) AF: 0.0238 AC: 137 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12934 AN: 1112008

Other (OTH) AF: 0.0133 AC: 805 AN: 60396

GnomAD4 genome AF: 0.0102 AC: 1558 AN: 152270 Hom.: 16 Cov.: 31 AF XY: 0.0114 AC XY: 852 AN XY: 74460

African (AFR) AF: 0.00190 AC: 79 AN: 41538

American (AMR) AF: 0.00699 AC: 107 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0384 AC: 185 AN: 4816

European-Finnish (FIN) AF: 0.0243 AC: 258 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 845 AN: 68014

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.0113 Hom.: 6

Bravo AF: 0.00787

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0151

EpiControl AF: 0.0148

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.9
DANN	Benign	0.72
PhyloP100		0.59
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45606837; hg19: chr2-219000460; COSMIC: COSV107386029; COSMIC: COSV107386029;