16-57415192-C-T

Variant names:

• chr16-57415192-C-T
• rs1902850306
• NM_002987.3:c.182C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002987.3(CCL17):​c.182C>T​(p.Ala61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCL17 NM_002987.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

CCL17 (HGNC:10615): (C-C motif chemokine ligand 17) This antimicrobial gene is one of several Cys-Cys (CC) cytokine genes clustered on the q arm of chromosome 16. 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 T lymphocytes, but not monocytes or granulocytes. The product of this gene binds to chemokine receptors CCR4 and CCR8. This chemokine plays important roles in T cell development in thymus as well as in trafficking and activation of mature T cells. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCL17	NM_002987.3	c.182C>T	p.Ala61Val	missense_variant	Exon 3 of 4	ENST00000219244.9	NP_002978.1
CCL17	XM_017023530.2	c.269C>T	p.Ala90Val	missense_variant	Exon 5 of 6		XP_016879019.1
CCL17	XM_011523256.3	c.266C>T	p.Ala89Val	missense_variant	Exon 5 of 6		XP_011521558.1
CCL17	XM_047434448.1	c.182C>T	p.Ala61Val	missense_variant	Exon 2 of 3		XP_047290404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCL17	ENST00000219244.9	c.182C>T	p.Ala61Val	missense_variant	Exon 3 of 4	1	NM_002987.3	ENSP00000219244.4
CCL17	ENST00000616880.1	c.182C>T	p.Ala61Val	missense_variant	Exon 2 of 3	1		ENSP00000480147.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448760 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182C>T (p.A61V) alteration is located in exon 3 (coding exon 2) of the CCL17 gene. This alteration results from a C to T substitution at nucleotide position 182, causing the alanine (A) at amino acid position 61 to be replaced by a valine (V). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.58
MutPred		0.84		Loss of catalytic residue at A61 (P = 0.0494);Loss of catalytic residue at A61 (P = 0.0494);
MVP		0.36
MPC		0.97
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.85

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: rs1902850306; hg19: chr16-57449104;