3-45947019-T-G

Variant names:

• chr3-45947019-T-G
• rs1559449498
• NM_006564.2:c.538T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006564.2(CXCR6):​c.538T>G​(p.Cys180Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C180R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR6 NM_006564.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR6	NM_006564.2	MANE Select	c.538T>G	p.Cys180Gly	missense	Exon 2 of 2	NP_006555.1	A0N0N3
	FYCO1	NM_024513.4	MANE Select	c.3944+8230A>C		intron	N/A	NP_078789.2	Q9BQS8-1
	CXCR6	NM_001386435.1		c.538T>G	p.Cys180Gly	missense	Exon 2 of 2	NP_001373364.1	O00574

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR6	ENST00000304552.5	TSL:1 MANE Select	c.538T>G	p.Cys180Gly	missense	Exon 2 of 2	ENSP00000304414.4	O00574
	CXCR6	ENST00000457814.1	TSL:1	c.538T>G	p.Cys180Gly	missense	Exon 2 of 2	ENSP00000396886.1	O00574
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.3944+8230A>C		intron	N/A	ENSP00000296137.2	Q9BQS8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.85		Loss of stability (P = 0.0539)
MVP		0.85
MPC		1.3
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.78
Mutation Taster		=9/91	disease causing

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: rs1559449498; hg19: chr3-45988511;