3-45947241-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006564.2(CXCR6):c.760C>T(p.Arg254Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CXCR6
NM_006564.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.199

Variant links:

Genes affected

CXCR6 (HGNC:16647): (C-X-C motif chemokine receptor 6) The protein encoded by this gene is a G protein-coupled receptor with seven transmembrane domains that belongs to the CXC chemokine receptor family. This family also includes CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR7. This gene, which maps to the chemokine receptor gene cluster, is expressed in several T lymphocyte subsets and bone marrow stromal cells. The encoded protein and its exclusive ligand, chemokine ligand 16 (CCL16), are part of a signalling pathway that regulates T lymphocyte migration to various peripheral tissues (the liver, spleen red pulp, intestine, lungs, and skin) and promotes cell-cell interaction with dendritic cells and fibroblastic reticular cells. CXCR6/CCL16 also controls the localization of resident memory T lymphocytes to different compartments of the lung and maintains airway resident memory T lymphocytes, which are an important first line of defense against respiratory pathogens. The encoded protein serves as an entry coreceptor used by HIV-1 and SIV to enter target cells, in conjunction with CD4. [provided by RefSeq, Aug 2020]

CXCR6 links:

FYCO1 (HGNC:14673): (FYVE and coiled-coil domain autophagy adaptor 1) The gene encodes a Rab7 adapter protein that is implicated in the microtubule transport of autophagosomes. The encoded protein contains a RUN domain, a FYVE-type zinc finger domain, and Golgi dynamics (GOLD) domain. The encoded protein plays a role in microtubule plus end-directed transport of autophagic vesicles through interactions with the small GTPase Rab7, phosphatidylinositol-3-phosphate (PI3P), the autophagosome marker LC3, and the kinesin KIF5. Mutations in this gene are associated with inclusion body myositis (IBM) and autosomal recessive congenital cataracts (CATC2). [provided by RefSeq, Aug 2020]

FYCO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19697812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR6	NM_006564.2 link	c.760C>T	p.Arg254Cys	missense_variant	Exon 2 of 2	ENST00000304552.5	NP_006555.1	O00574A0N0N3
FYCO1	NM_024513.4 link	c.3944+8008G>A		intron_variant	Intron 14 of 17	ENST00000296137.7	NP_078789.2	Q9BQS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR6	ENST00000304552.5 link	c.760C>T	p.Arg254Cys	missense_variant	Exon 2 of 2	1	NM_006564.2	ENSP00000304414.4		O00574
FYCO1	ENST00000296137.7 link	c.3944+8008G>A		intron_variant	Intron 14 of 17	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251248

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760C>T (p.R254C) alteration is located in exon 2 (coding exon 1) of the CXCR6 gene. This alteration results from a C to T substitution at nucleotide position 760, causing the arginine (R) at amino acid position 254 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

Benign

0.33

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.85

.;.;.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.2

M;M;M;M

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;D

Polyphen

0.68

P;P;P;P

Vest4

0.21

MutPred

0.50

Loss of catalytic residue at M250 (P = 0.1157);Loss of catalytic residue at M250 (P = 0.1157);Loss of catalytic residue at M250 (P = 0.1157);Loss of catalytic residue at M250 (P = 0.1157);

MVP

0.75

MPC

1.3

ClinPred

0.44

GERP RS

3.0

Varity_R

0.27

gMVP

0.86

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