3-46373570-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (93 hom.)
• Consequence: CCR5 NM_001394783.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.179

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

Verdict is Benign. Variant got -13 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 id is 8186.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCR5	NM_001394783.1	c.668G>A	p.Arg223Gln	missense_variant	2/2	ENST00000292303.5
CCR5AS	NR_125406.1	n.392-2153C>T		intron_variant, non_coding_transcript_variant
CCR5	NM_000579.4	c.668G>A	p.Arg223Gln	missense_variant	3/3
CCR5	NM_001100168.2	c.668G>A	p.Arg223Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCR5	ENST00000292303.5	c.668G>A	p.Arg223Gln	missense_variant	2/2	1	NM_001394783.1	P1
CCR5AS	ENST00000701879.1	n.174-2153C>T		intron_variant, non_coding_transcript_variant
CCR5	ENST00000445772.1	c.668G>A	p.Arg223Gln	missense_variant	1/1			P1
CCR5AS	ENST00000451485.2	n.392-2153C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00492 AC: 1235 AN: 250954 Hom.: 27 AF XY: 0.00461 AC XY: 625 AN XY: 135616

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 SAS exome AF: 0.00229

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

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00563

Gnomad4 EAS exome AF: 0.0615

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.000888

Gnomad4 OTH exome AF: 0.00277

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

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00244 Hom.: 8

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

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CCR5 POLYMORPHISM, ORIENTAL 2 Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.073
Sift	Benign	0.064	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.066	B;B
Vest4		0.044
MVP		0.41
ClinPred		0.031	T
GERP RS		4.8
Varity_R		0.37
gMVP		0.37

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: rs1800452; hg19: chr3-46415061;