3-45947450-C-A

Variant names:

• chr3-45947450-C-A
• rs1704695754
• NM_006564.2:c.969C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006564.2(CXCR6):​c.969C>A​(p.Asp323Glu) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR6 NM_006564.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.863

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040170014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR6	NM_006564.2	c.969C>A	p.Asp323Glu	missense_variant	Exon 2 of 2	ENST00000304552.5	NP_006555.1
FYCO1	NM_024513.4	c.3944+7799G>T		intron_variant	Intron 14 of 17	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR6	ENST00000304552.5	c.969C>A	p.Asp323Glu	missense_variant	Exon 2 of 2	1	NM_006564.2	ENSP00000304414.4
FYCO1	ENST00000296137.7	c.3944+7799G>T		intron_variant	Intron 14 of 17	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.969C>A (p.D323E) alteration is located in exon 2 (coding exon 1) of the CXCR6 gene. This alteration results from a C to A substitution at nucleotide position 969, causing the aspartic acid (D) at amino acid position 323 to be replaced by a glutamic acid (E). 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	0.095
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.2
DANN	Benign	0.96
DEOGEN2	Benign	0.032	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	.;.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;M;M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.028	B;B;B;B
Vest4		0.040
MutPred		0.20		Gain of phosphorylation at S325 (P = 0.2094);Gain of phosphorylation at S325 (P = 0.2094);Gain of phosphorylation at S325 (P = 0.2094);Gain of phosphorylation at S325 (P = 0.2094);
MVP		0.49
MPC		0.36
ClinPred		0.19	T
GERP RS		1.7
Varity_R		0.058
gMVP		0.15

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

Other links and lift over

dbSNP: rs1704695754; hg19: chr3-45988942;