NM_001296.5:c.1118A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001296.5(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
NM_001296.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.501

Publications

47 publications found

Variant links:

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]

ACKR2 links:

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]

CYP8B1 links:

ENSG00000290317 (HGNC:):

ENSG00000290317 links:

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ACMG classification

Classification was made for transcript

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: 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>T	p.Tyr373Phe	missense	Exon 3 of 3	NP_001287.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0110

AC XY:

7981

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33468

American (AMR)

AF:

0.00501

AC:

224

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

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:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0123

AC:

13625

AN:

1111696

Other (OTH)

AF:

0.00845

AC:

510

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

910

1820

2729

3639

4549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

544

1088

1632

2176

2720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00811

AC:

1232

AN:

151866

Hom.:

Cov.:

AF XY:

0.00756

AC XY:

561

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

41396

American (AMR)

AF:

0.00786

AC:

120

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.0100

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10542

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

817

AN:

67940

Other (OTH)

AF:

0.00569

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000188

Hom.:

39964

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0135

AC:

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

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.17

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.033

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.50

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.020

REVEL

Benign

0.12

Sift

Benign

0.63

Sift4G

Benign

0.28

Polyphen

0.0

Vest4

0.11

MVP

0.030

MPC

0.099

ClinPred

0.000055

GERP RS

0.69

Varity_R

0.051

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over