17-35878597-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001278736.2(CCL5):c.119G>A(p.Arg40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CCL5
NM_001278736.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.853

Variant links:

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]

CCL5 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032995164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCL5	NM_002985.3 linkuse as main transcript	c.119G>A	p.Arg40His	missense_variant	2/3	ENST00000605140.6
LOC105371745	XR_007065724.1 linkuse as main transcript	n.148-5785C>T		intron_variant, non_coding_transcript_variant
CCL5	NM_001278736.2 linkuse as main transcript	c.119G>A	p.Arg40His	missense_variant	2/4
LOC105371745	XR_934699.2 linkuse as main transcript	n.148-5785C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CCL5	ENST00000605140.6 linkuse as main transcript	c.119G>A	p.Arg40His	missense_variant	2/3	5	NM_002985.3	P1
	ENST00000605548.1 linkuse as main transcript	n.153-5785C>T		intron_variant, non_coding_transcript_variant		3
CCL5	ENST00000651122.1 linkuse as main transcript	c.119G>A	p.Arg40His	missense_variant	2/4
CCL5	ENST00000605509.2 linkuse as main transcript	c.119G>A	p.Arg40His	missense_variant	3/4	3		P1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

250824

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461396

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000191

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.000675

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000395

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.119G>A (p.R40H) alteration is located in exon 2 (coding exon 2) of the CCL5 gene. This alteration results from a G to A substitution at nucleotide position 119, causing the arginine (R) at amino acid position 40 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.65

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.28

M_CAP

Benign

0.0074

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.026

D;D

Polyphen

0.038

B;B

Vest4

0.20

MVP

0.42

ClinPred

0.28

GERP RS

2.1

Varity_R

0.40

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over