3-42864624-T-C

Position:

• chr3-42864624-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001296.5(ACKR2):​c.122T>C​(p.Val41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,614,140 control chromosomes in the GnomAD database, including 3,020 homozygotes. In-silico tool predicts 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 0.047 (233 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2787 hom.)
• Consequence: ACKR2 NM_001296.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027184486).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACKR2	NM_001296.5	c.122T>C	p.Val41Ala	missense_variant	3/3	ENST00000422265.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACKR2	ENST00000422265.6	c.122T>C	p.Val41Ala	missense_variant	3/3	1	NM_001296.5	P1

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7092 AN: 152154 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.0521

GnomAD3 exomes AF: 0.0508 AC: 12775 AN: 251474 Hom.: 411 AF XY: 0.0522 AC XY: 7098 AN XY: 135910

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0787

Gnomad NFE exome AF: 0.0713

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0577 AC: 84372 AN: 1461868 Hom.: 2787 Cov.: 30 AF XY: 0.0572 AC XY: 41596 AN XY: 727234

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0366

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.0640

Gnomad4 OTH exome AF: 0.0550

GnomAD4 genome AF: 0.0465 AC: 7087 AN: 152272 Hom.: 233 Cov.: 32 AF XY: 0.0456 AC XY: 3396 AN XY: 74450

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0478

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0730

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.0516

Alfa AF: 0.0638 Hom.: 841

Bravo AF: 0.0433

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0675 AC: 260

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0677 AC: 582

ExAC AF: 0.0507 AC: 6150

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0724

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;.;T;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	.;T;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.0	D;D;.;.;.;.
REVEL	Benign	0.087
Sift	Uncertain	0.011	D;D;.;.;.;.
Sift4G	Uncertain	0.040	D;D;D;T;T;D
Polyphen		0.96	D;D;.;.;.;.
Vest4		0.068
MPC		0.57
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.21

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: rs2228467; hg19: chr3-42906116; COSMIC: COSV56177366; COSMIC: COSV56177366;