rs2234671

Positions:

• chr2-218164385-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000634.3(CXCR1):​c.827G>C​(p.Ser276Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0719 in 1,613,424 control chromosomes in the GnomAD database, including 5,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1228 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4389 hom.)
• Consequence: CXCR1 NM_000634.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.04

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009817481).
• BP6: Variant 2-218164385-C-G is Benign according to our data. Variant chr2-218164385-C-G is described in ClinVar as [Benign]. Clinvar id is 2571396.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXCR1	NM_000634.3	c.827G>C	p.Ser276Thr	missense_variant	2/2	ENST00000295683.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXCR1	ENST00000295683.3	c.827G>C	p.Ser276Thr	missense_variant	2/2	1	NM_000634.3	P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16191 AN: 151972 Hom.: 1222 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0896

GnomAD3 exomes AF: 0.0910 AC: 22808 AN: 250754 Hom.: 1451 AF XY: 0.0883 AC XY: 11965 AN XY: 135506

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.0777

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.0567

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0722

GnomAD4 exome AF: 0.0683 AC: 99797 AN: 1461334 Hom.: 4389 Cov.: 32 AF XY: 0.0694 AC XY: 50420 AN XY: 726914

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.0356

Gnomad4 EAS exome AF: 0.0764

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0559

Gnomad4 OTH exome AF: 0.0747

GnomAD4 genome AF: 0.107 AC: 16214 AN: 152090 Hom.: 1228 Cov.: 32 AF XY: 0.109 AC XY: 8075 AN XY: 74356

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.0774

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0564

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.0689 Hom.: 165

Bravo AF: 0.114

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0594 AC: 229

ESP6500AA AF: 0.195 AC: 860

ESP6500EA AF: 0.0535 AC: 460

ExAC AF: 0.0913 AC: 11090

Asia WGS AF: 0.109 AC: 377 AN: 3478

EpiCase AF: 0.0535

EpiControl AF: 0.0532

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

CXCR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cholangiocarcinoma Other:1

other, no assertion criteria provided

research

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Dec 10, 2022

No association with disease-free or overall survival after resection of intrahepatic Cholangiocarcinoma No association with disease-free or overall survival

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.83
DANN	Benign	0.14
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.066
ClinPred		0.00018	T
GERP RS		1.8
Varity_R		0.031
gMVP		0.14

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: rs2234671; hg19: chr2-219029108; COSMIC: COSV55281069;