3-46373218-G-T

Variant names:

• chr3-46373218-G-T
• NM_001394783.1:c.316G>T

Variant summary

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

The NM_001394783.1(CCR5):​c.316G>T​(p.Gly106Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G106R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCR5 NM_001394783.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.74

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, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCR5	NM_001394783.1	c.316G>T	p.Gly106Trp	missense_variant	Exon 2 of 2	ENST00000292303.5	NP_001381712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCR5	ENST00000292303.5	c.316G>T	p.Gly106Trp	missense_variant	Exon 2 of 2	1	NM_001394783.1	ENSP00000292303.4
CCR5	ENST00000445772.1	c.316G>T	p.Gly106Trp	missense_variant	Exon 1 of 1	6		ENSP00000404881.1
CCR5AS	ENST00000451485.2	n.392-1801C>A		intron_variant	Intron 2 of 3	3
CCR5AS	ENST00000701879.1	n.174-1801C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.098	T;T
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.78		Gain of catalytic residue at L104 (P = 0.0055);Gain of catalytic residue at L104 (P = 0.0055);
MVP		0.69
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46414709;