rs333

Positions:

• chr3-46373452-TACAGTCAGTATCAATTCTGGAAGAATTTCCAG-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001394783.1(CCR5):​c.554_585del​(p.Ser185IlefsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0977 in 1,613,870 control chromosomes in the GnomAD database, including 8,868 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.072 (553 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8315 hom.)
• Consequence: CCR5 NM_001394783.1 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:4 O:2
• Conservation: PhyloP100: 0.894

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCR5	NM_001394783.1	c.554_585del	p.Ser185IlefsTer32	frameshift_variant	2/2	ENST00000292303.5	NP_001381712.1
CCR5AS	NR_125406.1	n.392-2067_392-2036del		intron_variant, non_coding_transcript_variant
CCR5	NM_000579.4	c.554_585del	p.Ser185IlefsTer32	frameshift_variant	3/3		NP_000570.1
CCR5	NM_001100168.2	c.554_585del	p.Ser185IlefsTer32	frameshift_variant	3/3		NP_001093638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCR5	ENST00000292303.5	c.554_585del	p.Ser185IlefsTer32	frameshift_variant	2/2	1	NM_001394783.1	ENSP00000292303	P1
CCR5AS	ENST00000701879.1	n.174-2067_174-2036del		intron_variant, non_coding_transcript_variant
CCR5	ENST00000445772.1	c.554_585del	p.Ser185IlefsTer32	frameshift_variant	1/1			ENSP00000404881	P1
CCR5AS	ENST00000451485.2	n.392-2067_392-2036del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10911 AN: 152034 Hom.: 553 Cov.: 31

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0743 AC: 18640 AN: 251006 Hom.: 966 AF XY: 0.0745 AC XY: 10108 AN XY: 135678

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0726

GnomAD4 exome AF: 0.100 AC: 146811 AN: 1461718 Hom.: 8315 AF XY: 0.0983 AC XY: 71450 AN XY: 727168

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0303

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.0877

GnomAD4 genome AF: 0.0717 AC: 10914 AN: 152152 Hom.: 553 Cov.: 31 AF XY: 0.0707 AC XY: 5259 AN XY: 74390

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0929 Hom.: 121

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0915

EpiControl AF: 0.0970

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

CCR5-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Susceptibility to HIV infection Benign:1

protective, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2019

- -

Resistance to hepatitis C virus Benign:1

protective, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

West Nile virus, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Multiple sclerosis modifier of disease progression Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs333; hg19: chr3-46414943;