17-35878628-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278736.2(CCL5):c.88A>G(p.Thr30Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CCL5 NM_001278736.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

CCL5 (HGNC:10632): (C-C motif chemokine ligand 5) This 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 the N-terminal cysteine residues of the mature peptide. This chemokine, a member of the CC subfamily, functions as a chemoattractant for blood monocytes, memory T helper cells and eosinophils. It causes the release of histamine from basophils and activates eosinophils. This cytokine is one of the major HIV-suppressive factors produced by CD8+ cells. It functions as one of the natural ligands for the chemokine receptor chemokine (C-C motif) receptor 5 (CCR5), and it suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL5	NM_002985.3	c.88A>G	p.Thr30Ala	missense_variant	2/3	ENST00000605140.6
LOC105371745	XR_007065724.1	n.148-5754T>C		intron_variant, non_coding_transcript_variant
CCL5	NM_001278736.2	c.88A>G	p.Thr30Ala	missense_variant	2/4
LOC105371745	XR_934699.2	n.148-5754T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL5	ENST00000605140.6	c.88A>G	p.Thr30Ala	missense_variant	2/3	5	NM_002985.3	P1
	ENST00000605548.1	n.153-5754T>C		intron_variant, non_coding_transcript_variant		3
CCL5	ENST00000651122.1	c.88A>G	p.Thr30Ala	missense_variant	2/4
CCL5	ENST00000605509.2	c.88A>G	p.Thr30Ala	missense_variant	3/4	3		P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.88A>G (p.T30A) alteration is located in exon 2 (coding exon 2) of the CCL5 gene. This alteration results from a A to G substitution at nucleotide position 88, causing the threonine (T) at amino acid position 30 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.46	T;T
Polyphen		0.97	D;D
Vest4		0.49
MutPred		0.45		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.63
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.27

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: rs759918234; hg19: chr17-34205632;