chr3-42865620-A-C

Position:

• chr3-42865620-A-C

Variant summary

Our verdict is Benign. Variant got -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. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACKR2	NM_001296.5	c.1118A>C	p.Tyr373Ser	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>C	p.Tyr373Ser	missense_variant	3/3	1	NM_001296.5	ENSP00000416996.1
ENSG00000290317	ENST00000426937.5	c.-163-43173A>C		intron_variant		3		ENSP00000413859.1

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

GnomAD3 exomes AF: 0.434 AC: 108564 AN: 250288 Hom.: 26082 AF XY: 0.425 AC XY: 57469 AN XY: 135206

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 SAS exome AF: 0.396

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

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.635

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.397

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

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.375

Gnomad4 EAS AF: 0.667

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.346

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.409

Alfa AF: 0.386 Hom.: 26870

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 v4.3

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;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;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.4	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.57	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.026
MPC		0.16
ClinPred		0.0052	T
GERP RS		0.69
Varity_R		0.039
gMVP		0.20

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: COSV56177504; COSMIC: COSV56177504;