2-218164209-G-A

Variant names:

• chr2-218164209-G-A
• rs16858808
• NM_000634.3:c.1003C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• 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
• Publications: 33 publications found

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

Our verdict: Benign. The variant received -9 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000634.3. 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
	CXCR1	NM_000634.3	MANE Select	c.1003C>T	p.Arg335Cys	missense	Exon 2 of 2	NP_000625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR1	ENST00000295683.3	TSL:1 MANE Select	c.1003C>T	p.Arg335Cys	missense	Exon 2 of 2	ENSP00000295683.2

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

GnomAD2 exomes AF: 0.0271 AC: 6807 AN: 251256 AF XY: 0.0283

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 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

African (AFR) AF: 0.00520 AC: 174 AN: 33480

American (AMR) AF: 0.0190 AC: 851 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 1505 AN: 26134

East Asian (EAS) AF: 0.0158 AC: 627 AN: 39686

South Asian (SAS) AF: 0.0289 AC: 2491 AN: 86256

European-Finnish (FIN) AF: 0.0227 AC: 1212 AN: 53418

Middle Eastern (MID) AF: 0.0300 AC: 173 AN: 5768

European-Non Finnish (NFE) AF: 0.0300 AC: 33346 AN: 1111990

Other (OTH) AF: 0.0312 AC: 1883 AN: 60396

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

African (AFR) AF: 0.00611 AC: 254 AN: 41540

American (AMR) AF: 0.0203 AC: 310 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.0258 AC: 134 AN: 5184

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4826

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0314 AC: 2139 AN: 68018

Other (OTH) AF: 0.0288 AC: 61 AN: 2116

Alfa AF: 0.0309 Hom.: 350

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 v4.9

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
PhyloP100		1.5
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
Mutation Taster		=100/0	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: rs16858808; hg19: chr2-219028932; COSMIC: COSV99826242;