3-46373089-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001394783.1(CCR5):c.187A>T(p.Ser63Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000891 in 1,614,204 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 2 hom. )

Consequence

CCR5
NM_001394783.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.99

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03200823).

BS2

High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCR5	NM_001394783.1 linkuse as main transcript	c.187A>T	p.Ser63Cys	missense_variant	2/2	ENST00000292303.5
CCR5AS	NR_125406.1 linkuse as main transcript	n.392-1672T>A		intron_variant, non_coding_transcript_variant
CCR5	NM_000579.4 linkuse as main transcript	c.187A>T	p.Ser63Cys	missense_variant	3/3
CCR5	NM_001100168.2 linkuse as main transcript	c.187A>T	p.Ser63Cys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CCR5	ENST00000292303.5 linkuse as main transcript	c.187A>T	p.Ser63Cys	missense_variant	2/2	1	NM_001394783.1	P1
CCR5AS	ENST00000701879.1 linkuse as main transcript	n.174-1672T>A		intron_variant, non_coding_transcript_variant
CCR5	ENST00000445772.1 linkuse as main transcript	c.187A>T	p.Ser63Cys	missense_variant	1/1			P1
CCR5AS	ENST00000451485.2 linkuse as main transcript	n.392-1672T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000835

AC:

210

AN:

251378

Hom.:

AF XY:

0.000839

AC XY:

114

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.000913

AC:

1335

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000895

AC XY:

651

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000777

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00100

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152326

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000731

Hom.:

Bravo

AF:

0.000752

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000848

AC:

103

EpiCase

AF:

0.00158

EpiControl

AF:

0.00154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

West Nile virus, susceptibility to;C2675864:Type 1 diabetes mellitus 22

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 09, 2020

CCR5 NM_000579.3 exon 3 p.Ser63Cys (c.187A>T):This variant has not been reported in the literature but is present in 0.09% (127/129102) of European alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-46414580-A-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Hepatitis C virus, susceptibility to;C1835867:West Nile virus, susceptibility to;C1836230:Susceptibility to HIV infection;C2675864:Type 1 diabetes mellitus 22

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.021

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.022

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

0.50

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.21

B;B

Vest4

0.24

MVP

0.56

ClinPred

0.090

GERP RS

4.3

Varity_R

0.36

gMVP

0.53

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