17-34256250-T-C

Variant names:

• chr17-34256250-T-C
• rs4586
• NM_002982.4:c.105T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_002982.4(CCL2):​c.105T>C​(p.Cys35Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,609,614 control chromosomes in the GnomAD database, including 133,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.47 (18471 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114846 hom.)
• Consequence: CCL2 NM_002982.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.394

Genes affected

CCL2 (HGNC:10618): (C-C motif chemokine ligand 2) This gene is one of several cytokine genes clustered on the q-arm of chromosome 17. Chemokines are a superfamily of secreted proteins involved in immunoregulatory and inflammatory processes. The superfamily is divided into four subfamilies based on the arrangement of N-terminal cysteine residues of the mature peptide. This chemokine is a member of the CC subfamily which is characterized by two adjacent cysteine residues. This cytokine displays chemotactic activity for monocytes and basophils but not for neutrophils or eosinophils. It has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis and atherosclerosis. It binds to chemokine receptors CCR2 and CCR4. Elevated expression of the encoded protein is associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. [provided by RefSeq, Aug 2020]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-34256250-T-C is Benign according to our data. Variant chr17-34256250-T-C is described in ClinVar as [Benign]. Clinvar id is 3059105.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.394 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCL2	NM_002982.4	c.105T>C	p.Cys35Cys	synonymous_variant	Exon 2 of 3	ENST00000225831.4	NP_002973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCL2	ENST00000225831.4	c.105T>C	p.Cys35Cys	synonymous_variant	Exon 2 of 3	1	NM_002982.4	ENSP00000225831.4
CCL2	ENST00000580907.6	c.105T>C	p.Cys35Cys	synonymous_variant	Exon 2 of 2	2		ENSP00000462156.1
CCL2	ENST00000624362.2	n.966T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72025 AN: 151884 Hom.: 18430 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.458

GnomAD2 exomes AF: 0.444 AC: 111431 AN: 250930 AF XY: 0.431

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.554

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.388 AC: 565637 AN: 1457608 Hom.: 114846 Cov.: 31 AF XY: 0.388 AC XY: 281380 AN XY: 725212

Gnomad4 AFR exome AF: 0.676 AC: 22559 AN: 33388

Gnomad4 AMR exome AF: 0.597 AC: 26654 AN: 44674

Gnomad4 ASJ exome AF: 0.354 AC: 9229 AN: 26100

Gnomad4 EAS exome AF: 0.611 AC: 24224 AN: 39646

Gnomad4 SAS exome AF: 0.453 AC: 38973 AN: 86074

Gnomad4 FIN exome AF: 0.408 AC: 21783 AN: 53364

Gnomad4 NFE exome AF: 0.357 AC: 395473 AN: 1108390

Gnomad4 Remaining exome AF: 0.403 AC: 24284 AN: 60218

GnomAD4 genome AF: 0.474 AC: 72121 AN: 152006 Hom.: 18471 Cov.: 32 AF XY: 0.478 AC XY: 35499 AN XY: 74310

Gnomad4 AFR AF: 0.665 AC: 0.665011 AN: 0.665011

Gnomad4 AMR AF: 0.540 AC: 0.540016 AN: 0.540016

Gnomad4 ASJ AF: 0.355 AC: 0.354792 AN: 0.354792

Gnomad4 EAS AF: 0.557 AC: 0.557243 AN: 0.557243

Gnomad4 SAS AF: 0.454 AC: 0.45447 AN: 0.45447

Gnomad4 FIN AF: 0.409 AC: 0.409358 AN: 0.409358

Gnomad4 NFE AF: 0.359 AC: 0.358898 AN: 0.358898

Gnomad4 OTH AF: 0.455 AC: 0.454976 AN: 0.454976

Alfa AF: 0.396 Hom.: 37062

Bravo AF: 0.493

Asia WGS AF: 0.508 AC: 1769 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.359

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CCL2-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.6
DANN	Benign	0.41
Mutation Taster		=98/2	polymorphism (auto)

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: rs4586; hg19: chr17-32583269; COSMIC: COSV56773536; COSMIC: COSV56773536;