3-45946488-G-A

Variant names:

• chr3-45946488-G-A
• rs2234355
• NM_006564.2:c.7G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006564.2(CXCR6):​c.7G>A​(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 1,612,094 control chromosomes in the GnomAD database, including 7,714 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (4086 hom., cov: 32)
  • Exomes 𝑓: 0.014 (3628 hom.)
• Consequence: CXCR6 NM_006564.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 20 publications found

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]

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 Gene-Disease associations (from GenCC):

• cataract 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.6104193E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006564.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR6	NM_006564.2	MANE Select	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	NP_006555.1
	FYCO1	NM_024513.4	MANE Select	c.3944+8761C>T		intron	N/A	NP_078789.2
	CXCR6	NM_001386435.1		c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	NP_001373364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR6	ENST00000304552.5	TSL:1 MANE Select	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	ENSP00000304414.4
	CXCR6	ENST00000457814.1	TSL:1	c.7G>A	p.Glu3Lys	missense	Exon 2 of 2	ENSP00000396886.1
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.3944+8761C>T		intron	N/A	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19210 AN: 152088 Hom.: 4086 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0899

GnomAD2 exomes AF: 0.0338 AC: 8474 AN: 250474 AF XY: 0.0253

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000979

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0138 AC: 20118 AN: 1459888 Hom.: 3628 Cov.: 31 AF XY: 0.0121 AC XY: 8800 AN XY: 725974

African (AFR) AF: 0.451 AC: 15083 AN: 33428

American (AMR) AF: 0.0251 AC: 1121 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00984 AC: 256 AN: 26016

East Asian (EAS) AF: 0.000429 AC: 17 AN: 39650

South Asian (SAS) AF: 0.00303 AC: 261 AN: 86062

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53366

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5766

European-Non Finnish (NFE) AF: 0.00130 AC: 1446 AN: 1110570

Other (OTH) AF: 0.0298 AC: 1800 AN: 60326

GnomAD4 genome AF: 0.126 AC: 19241 AN: 152206 Hom.: 4086 Cov.: 32 AF XY: 0.121 AC XY: 9006 AN XY: 74456

African (AFR) AF: 0.436 AC: 18069 AN: 41446

American (AMR) AF: 0.0510 AC: 781 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68024

Other (OTH) AF: 0.0889 AC: 188 AN: 2114

Alfa AF: 0.114 Hom.: 2871

Bravo AF: 0.145

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.418 AC: 1842

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.0414 AC: 5028

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00208

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.00046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
Polyphen		0.68	P
Vest4		0.058
MPC		0.49
ClinPred		0.017	T
GERP RS		3.8
Varity_R		0.051
gMVP		0.21
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2234355; hg19: chr3-45987980;