17-36070991-A-G

Variant names:

• chr17-36070991-A-G
• rs149506889
• NM_002988.4:c.220A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002988.4(CCL18):​c.220A>G​(p.Asn74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: CCL18 NM_002988.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.290
• Publications: 3 publications found

Genes affected

CCL18 (HGNC:10616): (C-C motif chemokine ligand 18) This antimicrobial gene is one of several Cys-Cys (CC) cytokine genes clustered on the q arm of chromosome 17. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene displays chemotactic activity for naive T cells, CD4+ and CD8+ T cells and nonactivated lymphocytes, but not for monocytes or granulocytes. This chemokine attracts naive T lymphocytes toward dendritic cells and activated macrophages in lymph nodes. It may play a role in both humoral and cell-mediated immunity responses. [provided by RefSeq, Sep 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05733928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCL18	NM_002988.4	c.220A>G	p.Asn74Asp	missense_variant	Exon 3 of 3	ENST00000616054.2	NP_002979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCL18	ENST00000616054.2	c.220A>G	p.Asn74Asp	missense_variant	Exon 3 of 3	1	NM_002988.4	ENSP00000479955.1
CCL18	ENST00000616474.1	n.226A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251344 AF XY: 0.000317

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000569 AC: 832 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000556 AC XY: 404 AN XY: 727198

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000725 AC: 806 AN: 1111928

Other (OTH) AF: 0.000364 AC: 22 AN: 60392

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74322

African (AFR) AF: 0.000217 AC: 9 AN: 41442

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.220A>G (p.N74D) alteration is located in exon 3 (coding exon 3) of the CCL18 gene. This alteration results from a A to G substitution at nucleotide position 220, causing the asparagine (N) at amino acid position 74 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.045	N
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.29
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.24	T
Polyphen		0.43	B
Vest4		0.11
MVP		0.31
ClinPred		0.023	T
GERP RS		2.2
Varity_R		0.15
gMVP		0.19
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs149506889; hg19: chr17-34398351;