3-42865620-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000422265.6(ACKR2):​c.1118A>T​(p.Tyr373Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,126 control chromosomes in the GnomAD database, including 103 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 0.0081 (15 hom., cov: 31)
  • Exomes 𝑓: 0.011 (88 hom.)
• Consequence: ACKR2 ENST00000422265.6 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063323975).
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000422265.6. 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>T	p.Tyr373Phe	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>T	p.Tyr373Phe	missense	Exon 3 of 3	ENSP00000416996.1
	ACKR2	ENST00000442925.5	TSL:1	c.1118A>T	p.Tyr373Phe	missense	Exon 2 of 2	ENSP00000396150.1
	CYP8B1	ENST00000437102.1	TSL:1	c.1347+8850T>A		intron	N/A	ENSP00000404499.1

Frequencies

GnomAD3 genomes AF: 0.00811 AC: 1231 AN: 151748 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00787

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00978

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00826 AC: 2068 AN: 250288 AF XY: 0.00854

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00820

GnomAD4 exome AF: 0.0111 AC: 16198 AN: 1461260 Hom.: 88 Cov.: 52 AF XY: 0.0110 AC XY: 7981 AN XY: 726880

African (AFR) AF: 0.00173 AC: 58 AN: 33468

American (AMR) AF: 0.00501 AC: 224 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0116 AC: 995 AN: 86126

European-Finnish (FIN) AF: 0.0121 AC: 646 AN: 53394

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5762

European-Non Finnish (NFE) AF: 0.0123 AC: 13625 AN: 1111696

Other (OTH) AF: 0.00845 AC: 510 AN: 60362

GnomAD4 genome AF: 0.00811 AC: 1232 AN: 151866 Hom.: 15 Cov.: 31 AF XY: 0.00756 AC XY: 561 AN XY: 74222

African (AFR) AF: 0.00215 AC: 89 AN: 41396

American (AMR) AF: 0.00786 AC: 120 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.0100 AC: 48 AN: 4800

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10542

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 817 AN: 67940

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.000188 Hom.: 39964

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0135 AC: 52

ExAC AF: 0.00873 AC: 1060

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.17
DANN	Benign	0.23
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.50
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.12
Sift	Benign	0.63	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.030
MPC		0.099
ClinPred		0.000055	T
GERP RS		0.69
Varity_R		0.051
gMVP		0.11
Mutation Taster		=99/1	polymorphism

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: COSV56179629; COSMIC: COSV56179629;