chr3-46373543-A-G

Position:

• chr3-46373543-A-G

Variant summary

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

The NM_001394783.1(CCR5):​c.641A>G​(p.Tyr214Cys) variant causes a missense change involving the alteration of a 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)
• Consequence: CCR5 NM_001394783.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

CCR5 (HGNC:1606): (C-C motif chemokine receptor 5) This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. This protein is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells. Defective alleles of this gene have been associated with the HIV infection resistance. The ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Expression of this gene was also detected in a promyeloblastic cell line, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation. This gene is located at the chemokine receptor gene cluster region. An allelic polymorphism in this gene results in both functional and non-functional alleles; the reference genome represents the functional allele. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2015]

CCR5AS (HGNC:54398): (CCR5 antisense RNA)

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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCR5	NM_001394783.1	c.641A>G	p.Tyr214Cys	missense_variant	2/2	ENST00000292303.5	NP_001381712.1
CCR5AS	NR_125406.1	n.392-2126T>C		intron_variant, non_coding_transcript_variant
CCR5	NM_000579.4	c.641A>G	p.Tyr214Cys	missense_variant	3/3		NP_000570.1
CCR5	NM_001100168.2	c.641A>G	p.Tyr214Cys	missense_variant	3/3		NP_001093638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCR5	ENST00000292303.5	c.641A>G	p.Tyr214Cys	missense_variant	2/2	1	NM_001394783.1	ENSP00000292303	P1
CCR5AS	ENST00000701879.1	n.174-2126T>C		intron_variant, non_coding_transcript_variant
CCR5	ENST00000445772.1	c.641A>G	p.Tyr214Cys	missense_variant	1/1			ENSP00000404881	P1
CCR5AS	ENST00000451485.2	n.392-2126T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 14, 2023

The c.641A>G (p.Y214C) alteration is located in exon 3 (coding exon 1) of the CCR5 gene. This alteration results from a A to G substitution at nucleotide position 641, causing the tyrosine (Y) at amino acid position 214 to be replaced by a cysteine (C). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.5	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.80		Loss of MoRF binding (P = 0.119);Loss of MoRF binding (P = 0.119);
MVP		0.87
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.88

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: rs1701701934; hg19: chr3-46415034;