chr3-46373224-T-C

Position:

chr3-46373224-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001394783.1(CCR5):c.322T>C(p.Tyr108His) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CCR5
NM_001394783.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Variant links:

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]

CCR5 links:

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

CCR5AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CCR5	NM_001394783.1 linkuse as main transcript	c.322T>C	p.Tyr108His	missense_variant	2/2	ENST00000292303.5	NP_001381712.1
CCR5AS	NR_125406.1 linkuse as main transcript	n.392-1807A>G		intron_variant, non_coding_transcript_variant
CCR5	NM_000579.4 linkuse as main transcript	c.322T>C	p.Tyr108His	missense_variant	3/3		NP_000570.1
CCR5	NM_001100168.2 linkuse as main transcript	c.322T>C	p.Tyr108His	missense_variant	3/3		NP_001093638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CCR5	ENST00000292303.5 linkuse as main transcript	c.322T>C	p.Tyr108His	missense_variant	2/2	1	NM_001394783.1	ENSP00000292303	P1
CCR5AS	ENST00000701879.1 linkuse as main transcript	n.174-1807A>G		intron_variant, non_coding_transcript_variant
CCR5	ENST00000445772.1 linkuse as main transcript	c.322T>C	p.Tyr108His	missense_variant	1/1			ENSP00000404881	P1
CCR5AS	ENST00000451485.2 linkuse as main transcript	n.392-1807A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251322

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00000410

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

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

Dec 23, 2023

The c.322T>C (p.Y108H) alteration is located in exon 3 (coding exon 1) of the CCR5 gene. This alteration results from a T to C substitution at nucleotide position 322, causing the tyrosine (Y) at amino acid position 108 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

.;D

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.31

Sift

Benign

0.038

D;D

Sift4G

Uncertain

0.039

D;D

Polyphen

1.0

D;D

Vest4

0.53

MutPred

0.63

Loss of catalytic residue at L103 (P = 0.0994);Loss of catalytic residue at L103 (P = 0.0994);

MVP

0.61

ClinPred

0.98

GERP RS

5.4

Varity_R

0.60

gMVP

0.68

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

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