rs1799863

Positions:

• chr3-46373066-T-A
• chr3-46373066-T-C
• chr3-46373066-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001394783.1(CCR5):​c.164T>A​(p.Leu55Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0193 in 1,614,198 control chromosomes in the GnomAD database, including 349 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 0.014 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (320 hom.)
• Consequence: CCR5 NM_001394783.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.26

Genes affected

CCR5 (HGNC:1606): (C-C motif chemokine receptor 5) This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. This protein is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells. Defective alleles of this gene have been associated with the HIV infection resistance. The ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Expression of this gene was also detected in a promyeloblastic cell line, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation. This gene is located at the chemokine receptor gene cluster region. An allelic polymorphism in this gene results in both functional and non-functional alleles; the reference genome represents the functional allele. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2015]

CCR5AS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008668691).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0141 (2142/152324) while in subpopulation NFE AF= 0.0224 (1523/68028). AF 95% confidence interval is 0.0215. There are 29 homozygotes in gnomad4. There are 962 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCR5	NM_001394783.1	c.164T>A	p.Leu55Gln	missense_variant	2/2	ENST00000292303.5	NP_001381712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCR5	ENST00000292303.5	c.164T>A	p.Leu55Gln	missense_variant	2/2	1	NM_001394783.1	ENSP00000292303.4
CCR5	ENST00000445772.1	c.164T>A	p.Leu55Gln	missense_variant	1/1	6		ENSP00000404881.1
CCR5AS	ENST00000451485.2	n.392-1649A>T		intron_variant		3
CCR5AS	ENST00000701879.1	n.174-1649A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2144 AN: 152206 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0136 AC: 3419 AN: 251422 Hom.: 30 AF XY: 0.0135 AC XY: 1829 AN XY: 135874

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0198 AC: 28987 AN: 1461874 Hom.: 320 Cov.: 32 AF XY: 0.0194 AC XY: 14119 AN XY: 727240

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0141 AC: 2142 AN: 152324 Hom.: 29 Cov.: 32 AF XY: 0.0129 AC XY: 962 AN XY: 74488

Gnomad4 AFR AF: 0.00527

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0224

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0212 Hom.: 29

Bravo AF: 0.0152

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0235 AC: 202

ExAC AF: 0.0127 AC: 1545

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0237

EpiControl AF: 0.0253

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.52
ClinPred		0.070	T
GERP RS		5.4
Varity_R		0.98
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1799863; hg19: chr3-46414557; COSMIC: COSV99068718;