rs16858808

Positions:

• chr2-218164209-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000634.3(CXCR1):​c.1003C>T​(p.Arg335Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,614,124 control chromosomes in the GnomAD database, including 790 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (741 hom.)
• Consequence: CXCR1 NM_000634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49

Genes affected

CXCR1 (HGNC:6026): (C-X-C motif chemokine receptor 1) 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. Knockout studies in mice suggested that this protein inhibits embryonic oligodendrocyte precursor migration in developing spinal cord. This gene, IL8RB, 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031591952).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0235 (3584/152272) while in subpopulation NFE AF= 0.0314 (2139/68018). AF 95% confidence interval is 0.0303. There are 49 homozygotes in gnomad4. There are 1755 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR1	NM_000634.3	c.1003C>T	p.Arg335Cys	missense_variant	2/2	ENST00000295683.3	NP_000625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR1	ENST00000295683.3	c.1003C>T	p.Arg335Cys	missense_variant	2/2	1	NM_000634.3	ENSP00000295683	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3585 AN: 152154 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0271 AC: 6807 AN: 251256 Hom.: 100 AF XY: 0.0283 AC XY: 3843 AN XY: 135770

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0258

Gnomad SAS exome AF: 0.0258

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.0309

Gnomad OTH exome AF: 0.0338

GnomAD4 exome AF: 0.0289 AC: 42262 AN: 1461852 Hom.: 741 Cov.: 31 AF XY: 0.0294 AC XY: 21352 AN XY: 727224

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.0576

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0312

GnomAD4 genome AF: 0.0235 AC: 3584 AN: 152272 Hom.: 49 Cov.: 32 AF XY: 0.0236 AC XY: 1755 AN XY: 74466

Gnomad4 AFR AF: 0.00611

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.0258

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0314

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0327 Hom.: 196

Bravo AF: 0.0218

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0314 AC: 270

ExAC AF: 0.0266 AC: 3227

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Benign	0.081	T
Sift4G	Uncertain	0.031	D
Polyphen		0.97	D
Vest4		0.14
MPC		0.42
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.10
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs16858808; hg19: chr2-219028932; COSMIC: COSV99826242;