rs1799864

chr3-46357717-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001123396.4(CCR2):c.190G>A(p.Val64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,940 control chromosomes in the GnomAD database, including 9,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1287 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7970 hom.)
• Consequence: CCR2 NM_001123396.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.13

Genes affected

CCR2 (HGNC:1603): (C-C motif chemokine receptor 2) The protein encoded by this gene is a receptor for monocyte chemoattractant protein-1, a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The encoded protein mediates agonist-dependent calcium mobilization and inhibition of adenylyl cyclase. This protein can also be a coreceptor with CD4 for HIV-1 infection. This gene is located in the chemokine receptor gene cluster region of chromosome 3. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017913282).
• BP6: Variant 3-46357717-G-A is Benign according to our data. Variant chr3-46357717-G-A is described in ClinVar as [Benign]. Clinvar id is 8267.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCR2	NM_001123396.4	c.190G>A	p.Val64Ile	missense_variant	2/2	ENST00000445132.3
CCR2	NM_001123041.3	c.190G>A	p.Val64Ile	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCR2	ENST00000445132.3	c.190G>A	p.Val64Ile	missense_variant	2/2	1	NM_001123396.4	P2
CCR2	ENST00000400888.2	c.190G>A	p.Val64Ile	missense_variant	1/2	1		A2
CCR2	ENST00000421659.1	c.190G>A	p.Val64Ile	missense_variant	3/3	4
CCR2	ENST00000465202.1	n.315-400G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18420 AN: 151958 Hom.: 1285 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.127 AC: 31797 AN: 251286 Hom.: 2499 AF XY: 0.121 AC XY: 16401 AN XY: 135828

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.204

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0942

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0943 AC: 137839 AN: 1461864 Hom.: 7970 Cov.: 32 AF XY: 0.0946 AC XY: 68798 AN XY: 727236

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0710

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.121 AC: 18445 AN: 152076 Hom.: 1287 Cov.: 32 AF XY: 0.123 AC XY: 9115 AN XY: 74344

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.130

Alfa AF: 0.105 Hom.: 1496

Bravo AF: 0.132

TwinsUK AF: 0.0769 AC: 285

ALSPAC AF: 0.0703 AC: 271

ESP6500AA AF: 0.158 AC: 495

ESP6500EA AF: 0.0920 AC: 659

ExAC AF: 0.126 AC: 15351

Asia WGS AF: 0.184 AC: 638 AN: 3478

EpiCase AF: 0.0955

EpiControl AF: 0.0912

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CCR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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

May 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	12
Dann	Uncertain	0.98
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.69	T;T;T;.
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	N;N;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.079	.;B;.;B
Vest4		0.080
MPC		0.20
ClinPred		0.0028	T
GERP RS		1.6
Varity_R		0.045
gMVP		0.10

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: rs1799864; hg19: chr3-46399208; COSMIC: COSV52748713;