rs2228468

Variant names:

• chr3-42865620-A-C
• rs2228468
• NM_001296.5:c.1118A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-42865620-A-C
• chr3-42865620-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001296.5(ACKR2):​c.1118A>C​(p.Tyr373Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,612,976 control chromosomes in the GnomAD database, including 128,827 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11146 hom., cov: 31)
  • Exomes 𝑓: 0.39 (117681 hom.)
• Consequence: ACKR2 NM_001296.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• Publications: 47 publications found

Genes affected

ACKR2 (HGNC:1565): (atypical chemokine receptor 2) This gene encodes a beta chemokine receptor, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptor-mediated signal transduction are critical for the recruitment of effector immune cells to the inflammation site. This gene is expressed in a range of tissues and hemopoietic cells. The expression of this receptor in lymphatic endothelial cells and overexpression in vascular tumors suggested its function in chemokine-driven recirculation of leukocytes and possible chemokine effects on the development and growth of vascular tumors. This receptor appears to bind the majority of beta-chemokine family members; however, its specific function remains unknown. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes. [provided by RefSeq, Jul 2008]

CYP8B1 (HGNC:2653): (cytochrome P450 family 8 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the conversion of 7 alpha-hydroxy-4-cholesten-3-one into 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one. The balance between these two steroids determines the relative amounts of cholic acid and chenodeoxycholic acid both of which are secreted in the bile and affect the solubility of cholesterol. This gene is unique among the cytochrome P450 genes in that it is intronless. [provided by RefSeq, Jul 2008]

ENSG00000290317 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.068632E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001296.5. 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
	ACKR2	NM_001296.5	MANE Select	c.1118A>C	p.Tyr373Ser	missense	Exon 3 of 3	NP_001287.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACKR2	ENST00000422265.6	TSL:1 MANE Select	c.1118A>C	p.Tyr373Ser	missense	Exon 3 of 3	ENSP00000416996.1
	ACKR2	ENST00000442925.5	TSL:1	c.1118A>C	p.Tyr373Ser	missense	Exon 2 of 2	ENSP00000396150.1
	CYP8B1	ENST00000437102.1	TSL:1	c.1347+8850T>G		intron	N/A	ENSP00000404499.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55808 AN: 151682 Hom.: 11135 Cov.: 31

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.407

GnomAD2 exomes AF: 0.434 AC: 108564 AN: 250288 AF XY: 0.425

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.684

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.395 AC: 576509 AN: 1461176 Hom.: 117681 Cov.: 52 AF XY: 0.392 AC XY: 285182 AN XY: 726834

African (AFR) AF: 0.255 AC: 8518 AN: 33466

American (AMR) AF: 0.665 AC: 29696 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 9404 AN: 26066

East Asian (EAS) AF: 0.635 AC: 25202 AN: 39694

South Asian (SAS) AF: 0.393 AC: 33834 AN: 86116

European-Finnish (FIN) AF: 0.351 AC: 18735 AN: 53394

Middle Eastern (MID) AF: 0.395 AC: 2274 AN: 5762

European-Non Finnish (NFE) AF: 0.382 AC: 424884 AN: 1111650

Other (OTH) AF: 0.397 AC: 23962 AN: 60362

GnomAD4 genome AF: 0.368 AC: 55842 AN: 151800 Hom.: 11146 Cov.: 31 AF XY: 0.373 AC XY: 27704 AN XY: 74200

African (AFR) AF: 0.254 AC: 10505 AN: 41376

American (AMR) AF: 0.540 AC: 8232 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1299 AN: 3468

East Asian (EAS) AF: 0.667 AC: 3430 AN: 5142

South Asian (SAS) AF: 0.416 AC: 1993 AN: 4792

European-Finnish (FIN) AF: 0.346 AC: 3645 AN: 10534

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25486 AN: 67924

Other (OTH) AF: 0.409 AC: 862 AN: 2108

Alfa AF: 0.383 Hom.: 39964

Bravo AF: 0.387

TwinsUK AF: 0.371 AC: 1376

ALSPAC AF: 0.384 AC: 1480

ESP6500AA AF: 0.255 AC: 1123

ESP6500EA AF: 0.395 AC: 3397

ExAC AF: 0.419 AC: 50844

EpiCase AF: 0.385

EpiControl AF: 0.392

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.13
DANN	Benign	0.60
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0000091	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.4	N
PhyloP100		-0.50
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.16
ClinPred		0.0052	T
GERP RS		0.69
Varity_R		0.039
gMVP		0.20
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: rs2228468; hg19: chr3-42907112; COSMIC: COSV56177504; COSMIC: COSV56177504;