2-218164374-G-A

Variant names:

• chr2-218164374-G-A
• rs61755739
• NM_000634.3:c.838C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000634.3(CXCR1):​c.838C>T​(p.Arg280Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CXCR1 NM_000634.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36368775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR1	NM_000634.3	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2	ENST00000295683.3	NP_000625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR1	ENST00000295683.3	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2	1	NM_000634.3	ENSP00000295683.2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 250724 AF XY: 0.000192

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 354 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 726898

Gnomad4 AFR exome AF: 0.0000597 AC: 2 AN: 33476

Gnomad4 AMR exome AF: 0.000157 AC: 7 AN: 44712

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26104

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39686

Gnomad4 SAS exome AF: 0.000104 AC: 9 AN: 86242

Gnomad4 FIN exome AF: 0.0000749 AC: 4 AN: 53400

Gnomad4 NFE exome AF: 0.000291 AC: 323 AN: 1111608

Gnomad4 Remaining exome AF: 0.0000994 AC: 6 AN: 60380

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74434

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240755 AN: 0.0000240755

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207469 AN: 0.000207469

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000382 AC: 0.000382297 AN: 0.000382297

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000309 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Susceptibility to HIV infection Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CXCR1 NM_000634.2 exon 2 p.Arg280Cys (c.838C>T): This variant has not been reported in the literature but is present in 0.02% (38/128626) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-219029097-G-A?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.72
MPC		0.46
ClinPred		0.32	T
GERP RS		4.0
Varity_R		0.59
gMVP		0.36
Mutation Taster		=30/70	disease causing

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: rs61755739; hg19: chr2-219029097; COSMIC: COSV55281191;