XK

protein-coding

X-linked Kx blood group antigen, Kell and VPS13A binding protein, the group of XK related family|Blood group antigens

Gene summary

This locus controls the synthesis of the Kell blood group 'precursor substance' (Kx). Mutations in this gene have been associated with McLeod syndrome, an X-linked, recessive disorder characterized by abnormalities in the neuromuscular and hematopoietic systems. The encoded protein has structural characteristics of prokaryotic and eukaryotic membrane transport proteins. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_021083.4

Inheritance

ClinVar variants

P:17U:86B:42

Top phenotype

McLeod syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:37,685,791-37,732,130

External References & Databases

Ensembl (ENSG00000047597)

Transcript & Mutation Effects

hg38 • Region Span ~46.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

XK-related neurodegenerative diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0018945

Submitter: Labcorp Genetics (formerly Invitae)

XK-related neurodegenerative diseaseSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018945

Submitter: Orphanet

Clinical Genomic Database (CGD)

McLeod syndromeXL

Manifestation: Cardiovascular; Hematologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Surveillance for cardiovascular disease (eg, dilated cardiomyopathy and arrhythmias) and early medical treatment may reduce morbidity

Refs: 13860532; 8004674; 11261514; 11761473; 17683354; 21463873

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XK variants in ClinVar

7 Conditions Cataloged

not providedTotal: 64

Inborn genetic diseasesTotal: 34

not specifiedTotal: 28

XK-related neurodegenerative diseaseTotal: 27

XK-related disorderTotal: 4

XK-related disordersTotal: 2

Elevated circulating creatine kinase activityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021083.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	29 clinvar	3 clinvar	34
missense	1 clinvar		77 clinvar	9 clinvar	1 clinvar	88
nonsense	6 clinvar	2 clinvar	4 clinvar			12
start loss						0
frameshift	4 clinvar	1 clinvar				5
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	3 clinvar			6
Total	13	4	86	38	4	145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021083.4	RefSeq	NP_066569.1	3	MANE Select
ENST00000378616.5	Ensembl	ENSP00000367879.3	3	MANE Select
ENST00001121873.1	Ensembl	ENSP00000791678.1	4	Standard
XM_011543978.4	RefSeq	XP_011542280.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Peptide ligand-binding receptors
Class A/1 (Rhodopsin-like receptors)
GPCR ligand binding

Biological Process

amino acid transport
cellular calcium ion homeostasis
regulation of cell size
cellular magnesium ion homeostasis
regulation of axon diameter

Molecular Function

transporter activity
protein binding

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378616
Coding exons: 3
Length: 46372
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.12	88	165	0.534	0.0000113	2892
Missense (PolyPhen)		26	67.343	0.38608		1187
Synonymous	-0.633	80	73.1	1.09	0.00000542	907
Loss of Function	2.88	0	9.65	0.00	6.68e-7	159

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in sodium-dependent transport of neutral amino acids or oligopeptides.;
Disease: DISEASE: McLeod syndrome (MLS) [MIM:300842]: A multisystem disorder characterized by the absence of red blood cell Kx antigen, weak expression of Kell red blood cell antigens, acanthocytosis, and compensated hemolysis. Most carriers of this McLeod blood group phenotype have acanthocytosis and elevated serum creatine kinase levels and are prone to develop a severe neurologic disorder resembling Huntington disease. Additional symptoms include generalized seizures, neuromuscular symptoms leading to weakness and atrophy, and cardiomyopathy mainly manifesting with atrial fibrillation, malignant arrhythmias, and dilated cardiomyopathy. {ECO:0000269|PubMed:11761473, ECO:0000269|PubMed:11961232, ECO:0000269|PubMed:12823753}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.158

Intolerance Scores

RVIS EVS: -0.05
RVIS percentile EVS: 49.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Low	Medium