chr3-42865620-A-T

Position:

• chr3-42865620-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y373S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (15 hom., cov: 31)
  • Exomes 𝑓: 0.011 (88 hom.)
• Consequence: ACKR2 NM_001296.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501

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

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACKR2	NM_001296.5	c.1118A>T	p.Tyr373Phe	missense_variant	3/3	ENST00000422265.6	NP_001287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACKR2	ENST00000422265.6	c.1118A>T	p.Tyr373Phe	missense_variant	3/3	1	NM_001296.5	ENSP00000416996.1
ENSG00000290317	ENST00000426937.5	c.-163-43173A>T		intron_variant		3		ENSP00000413859.1

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

GnomAD3 exomes AF: 0.00826 AC: 2068 AN: 250288 Hom.: 12 AF XY: 0.00854 AC XY: 1155 AN XY: 135206

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 SAS exome AF: 0.0110

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

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00845

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

Gnomad4 AFR AF: 0.00215

Gnomad4 AMR AF: 0.00786

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0100

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.000285 Hom.: 26870

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 v4.3

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;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;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.12
Sift	Benign	0.63	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;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

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: rs2228468; hg19: chr3-42907112; COSMIC: COSV56179629; COSMIC: COSV56179629;