rs1133763

Positions:

• chr17-34320812-A-C
• chr17-34320812-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005623.3(CCL8):​c.205A>C​(p.Lys69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,601,202 control chromosomes in the GnomAD database, including 27,316 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2210 hom., cov: 32)
  • Exomes 𝑓: 0.17 (25106 hom.)
• Consequence: CCL8 NM_005623.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96

Genes affected

CCL8 (HGNC:10635): (C-C motif chemokine ligand 8) This antimicrobial gene is one of several chemokine genes clustered on the q-arm of chromosome 17. Chemokines form 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, lymphocytes, basophils and eosinophils. By recruiting leukocytes to sites of inflammation this cytokine may contribute to tumor-associated leukocyte infiltration and to the antiviral state against HIV infection. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001110673).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCL8	NM_005623.3	c.205A>C	p.Lys69Gln	missense_variant	3/3	ENST00000394620.2	NP_005614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCL8	ENST00000394620.2	c.205A>C	p.Lys69Gln	missense_variant	3/3	1	NM_005623.3	ENSP00000378118.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22940 AN: 152050 Hom.: 2201 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.207 AC: 50140 AN: 242118 Hom.: 6348 AF XY: 0.210 AC XY: 27624 AN XY: 131232

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.174 AC: 252455 AN: 1449034 Hom.: 25106 Cov.: 30 AF XY: 0.180 AC XY: 129455 AN XY: 721154

Gnomad4 AFR exome AF: 0.0606

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.151 AC: 22980 AN: 152168 Hom.: 2210 Cov.: 32 AF XY: 0.157 AC XY: 11684 AN XY: 74408

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.161

Alfa AF: 0.163 Hom.: 2801

Bravo AF: 0.152

TwinsUK AF: 0.164 AC: 607

ALSPAC AF: 0.155 AC: 596

ESP6500AA AF: 0.0722 AC: 318

ESP6500EA AF: 0.161 AC: 1384

ExAC AF: 0.204 AC: 24805

Asia WGS AF: 0.301 AC: 1046 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.34	T
REVEL	Benign	0.061
Sift4G	Benign	0.085	T
Polyphen		0.87	P
Vest4		0.088
MPC		0.57
ClinPred		0.045	T
GERP RS		3.1
Varity_R		0.24
gMVP		0.60

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: rs1133763; hg19: chr17-32647831; COSMIC: COSV67013983;