3-46373570-G-A

Variant names:

• chr3-46373570-G-A
• rs1800452
• NM_001394783.1:c.668G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001394783.1(CCR5):​c.668G>A​(p.Arg223Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,554 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (93 hom.)
• Consequence: CCR5 NM_001394783.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.179
• Publications: 32 publications found

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:54398): (CCR5 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027464628).
• BP6: Variant 3-46373570-G-A is Benign according to our data. Variant chr3-46373570-G-A is described in ClinVar as Benign. ClinVar VariationId is 8186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394783.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCR5	NM_001394783.1	MANE Select	c.668G>A	p.Arg223Gln	missense	Exon 2 of 2	NP_001381712.1	Q38L21
	CCR5AS	NR_125406.2	MANE Select	n.399-2153C>T		intron	N/A
	CCR5	NM_000579.4		c.668G>A	p.Arg223Gln	missense	Exon 3 of 3	NP_000570.1	Q38L21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCR5	ENST00000292303.5	TSL:1 MANE Select	c.668G>A	p.Arg223Gln	missense	Exon 2 of 2	ENSP00000292303.4	P51681
	CCR5AS	ENST00000451485.3	TSL:3 MANE Select	n.399-2153C>T		intron	N/A
	CCR5	ENST00000445772.1	TSL:6	c.668G>A	p.Arg223Gln	missense	Exon 1 of 1	ENSP00000404881.1	P51681

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152076 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00492 AC: 1235 AN: 250954 AF XY: 0.00461

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00538

Gnomad EAS exome AF: 0.0526

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00275 AC: 4021 AN: 1461360 Hom.: 93 Cov.: 32 AF XY: 0.00279 AC XY: 2025 AN XY: 726948

African (AFR) AF: 0.000179 AC: 6 AN: 33428

American (AMR) AF: 0.000358 AC: 16 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 147 AN: 26108

East Asian (EAS) AF: 0.0615 AC: 2443 AN: 39694

South Asian (SAS) AF: 0.00262 AC: 226 AN: 86236

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53400

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000888 AC: 987 AN: 1111682

Other (OTH) AF: 0.00277 AC: 167 AN: 60360

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152194 Hom.: 7 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74418

African (AFR) AF: 0.000169 AC: 7 AN: 41530

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.0521 AC: 269 AN: 5166

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00255 Hom.: 10

Bravo AF: 0.00326

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00502 AC: 610

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CCR5 POLYMORPHISM, ORIENTAL 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.18
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.073
Sift	Benign	0.064	T
Sift4G	Benign	0.15	T
Polyphen		0.066	B
Vest4		0.044
MVP		0.41
ClinPred		0.031	T
GERP RS		4.8
Varity_R		0.37
gMVP		0.37
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1800452; hg19: chr3-46415061;