KCNU1

protein-coding

potassium calcium-activated channel subfamily U member 1, the group of Potassium calcium-activated channels

Gene summary

This gene encodes a member of the potassium channel family of proteins. The encoded voltage-gated ion channel allows the outward flow of potassium ions during plasma membrane hyperpolarization in sperm. Opening of this channel may be regulated by calcium ion levels. Homozygous knockout mice that lack the related mouse gene exhibit male sterility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MANE transcript

NM_001031836.3

Inheritance

ClinVar variants

P:2U:155B:21

Top phenotype

Spermatogenic failure 79

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr8:36,784,324-36,936,125

External References & Databases

Ensembl (ENSG00000215262)

Transcript & Mutation Effects

hg38 • Region Span ~151.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 79LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859352

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spermatogenic failure 79AR

Manifestation: Genitourinary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision making, and avoidance of unnecessary testing

Refs: 34980136; 35551387

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNU1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 164

not providedTotal: 11

Spermatogenic failure 79Total: 3

KCNU1-related conditionTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001031836.3. 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			1 clinvar	1 clinvar	4 clinvar	6
missense	2 clinvar		153 clinvar	15 clinvar	1 clinvar	171
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	2	0	155	16	5	178

Highest pathogenic variant AF is 0.0000034254272

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001031836.3	RefSeq	NP_001027006.2	27	MANE Select
ENST00000399881.8	Ensembl	ENSP00000382770.3	27	MANE Select
ENST00000522372.5	Ensembl	ENSP00000428552.1	26	Standard
ENST00000522417.1	Ensembl	ENSP00000429149.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vascular smooth muscle contraction - Homo sapiens (human)
cGMP-PKG signaling pathway - Homo sapiens (human)
Insulin secretion - Homo sapiens (human)
Fertilization
Reproduction

Biological Process

reproductive process
regulation of ion transmembrane transport
sperm-egg recognition
regulation of membrane potential
potassium ion transmembrane transport

Molecular Function

potassium channel activity
calcium-activated potassium channel activity
outward rectifier potassium channel activity
large conductance calcium-activated potassium channel activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399881
Coding exons: 27
Length: 151805
Individuals with no LoFs: 124383
Homozygous LoFs: 0
Heterozygous LoFs: 261
Defined: 124644
p: 0.00105

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00508	598	598	0.999	0.0000308	7477
Missense (PolyPhen)		140	195.73	0.71526		2601
Synonymous	-1.23	248	225	1.10	0.0000119	2191
Loss of Function	2.70	34	55.7	0.610	0.00000291	686

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00059	0.00058	rare
Latino/Admixed American	0.00055	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00039	0.00039	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0017	0.0017	notable
South Asian	0.00036	0.00036	rare
Other	0.0012	0.0012	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Testis-specific potassium channel activated by both intracellular pH and membrane voltage that mediates export of K(+). May represent the primary spermatozoan K(+) current. In contrast to KCNMA1/SLO1, it is not activated by Ca(2+) or Mg(2+). Critical for fertility. May play an important role in sperm osmoregulation required for the acquisition of normal morphology and motility when faced with osmotic challenges, such as those experienced after mixing with seminal fluid and entry into the vagina. {ECO:0000269|PubMed:23129643}.;

Intolerance Scores

LoFtool: 0.534
RVIS EVS: -0.74
RVIS percentile EVS: 13.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.108

Gene Damage Prediction

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