CLCN7

chloride voltage-gated channel 7, the group of Chloride voltage-gated channels|Protein phosphatase 1 regulatory subunits

Basic information

Region (hg38): 16:1444933-1475077

Links

ENSG00000103249 ∙ NCBI:1186 ∙ OMIM:602727 ∙ HGNC:2025 ∙ Uniprot:P51798 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant osteopetrosis 2 (Supportive), mode of inheritance: AD
• autosomal recessive osteopetrosis (Supportive), mode of inheritance: AR
• autosomal recessive osteopetrosis 6 (Supportive), mode of inheritance: AR
• autosomal recessive osteopetrosis 4 (Strong), mode of inheritance: AR
• hypopigmentation, organomegaly, and delayed myelination and development (Strong), mode of inheritance: AD
• autosomal dominant osteopetrosis 2 (Strong), mode of inheritance: AD
• hypopigmentation, organomegaly, and delayed myelination and development (Moderate), mode of inheritance: AD
• autosomal dominant osteopetrosis 2 (Definitive), mode of inheritance: AD
• autosomal recessive osteopetrosis 4 (Definitive), mode of inheritance: AR
• autosomal recessive osteopetrosis 4 (Definitive), mode of inheritance: AR
• autosomal dominant osteopetrosis 2 (Strong), mode of inheritance: AD
• autosomal recessive osteopetrosis 4 (Strong), mode of inheritance: AR
• hypopigmentation, organomegaly, and delayed myelination and development (Limited), mode of inheritance: AD
• autosomal dominant osteopetrosis 2 (Limited), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4	AD/AR	Allergy/Immunology/Infectious; Hematologic; Musculoskeletal	In Autosomal recessive osteopetrosis, early diagnosis can allow medical treatment related to calcium homeostasis, including prevention/treatment of hypocalcemic seizures; Transfusions for hematologic manifestations may be necessary; Individuals may benefit from infectious prophylaxis and early and aggressive treatments of infections; HSCT has been described as beneficial; In Autosomal dominant forms of Osteopetrosis, avoidance of high-fracture risk activities can be beneficial, and calcitriol has been reported as beneficial	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	18131787; 13665485; 4871758; 6546410; 3377922; 2268972; 8358946; 10617161; 11741829; 11207362; 12522560; 13130312; 14584882; 17033731; 17164308; 20301306; 23296056; 31155284

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN7 gene.

• not provided (868 variants)
• Osteopetrosis (151 variants)
• Autosomal recessive osteopetrosis 4 (31 variants)
• Inborn genetic diseases (30 variants)
• Autosomal dominant osteopetrosis 2 (26 variants)
• not specified (21 variants)
• Hypopigmentation, organomegaly, and delayed myelination and development (16 variants)
• Increased bone mineral density (12 variants)
• Autosomal dominant osteopetrosis 2;Autosomal recessive osteopetrosis 4;Hypopigmentation, organomegaly, and delayed myelination and development (2 variants)
• Autosomal recessive osteopetrosis 4;Autosomal dominant osteopetrosis 2 (2 variants)
• Hypopigmentation, organomegaly, and delayed myelination and development;Autosomal recessive osteopetrosis 4;Autosomal dominant osteopetrosis 2 (2 variants)
• CLCN7-related condition (1 variants)
• Abnormality of the skeletal system (1 variants)
• See cases (1 variants)
• Hypopigmentation, organomegaly, and delayed myelination and development;Autosomal dominant osteopetrosis 2;Autosomal recessive osteopetrosis 4 (1 variants)
• Connective tissue disorder (1 variants)
• Autosomal dominant osteopetrosis 2;Hypopigmentation, organomegaly, and delayed myelination and development;Autosomal recessive osteopetrosis 4 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN7 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	193	14	213
missense	13	19	249	16	1	298
nonsense	5		1			6
start loss						0
frameshift	10	3				13
inframe indel			6			6
splice donor/acceptor (+/-2bp)	1	6	5			12
splice region			35	42	2	79
non coding	2		51	134	108	295
Total	31	28	318	343	123

Highest pathogenic variant AF is 0.0000328

Variants in CLCN7

This is a list of pathogenic ClinVar variants found in the CLCN7 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-1444946-C-T		Osteopetrosis	Likely benign (Jan 13, 2018)
16-1444964-G-A		Osteopetrosis	Uncertain significance (Jan 12, 2018)
16-1444986-C-G		Osteopetrosis	Benign (Jan 12, 2018)
16-1445005-C-G		Osteopetrosis	Benign (Jan 13, 2018)
16-1445006-AACC-A		Osteopetrosis	Likely benign (Jun 14, 2016)
16-1445008-C-A		Osteopetrosis	Uncertain significance (Jan 15, 2018)
16-1445024-C-A		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445042-C-G		Osteopetrosis	Likely benign (Jan 13, 2018)
16-1445058-C-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445059-G-A		Osteopetrosis	Likely benign (Jan 13, 2018)
16-1445133-G-GC		Osteopetrosis	Uncertain significance (Jun 14, 2016)
16-1445140-G-A		Osteopetrosis	Uncertain significance (Jan 12, 2018)
16-1445179-C-T		Osteopetrosis	Likely benign (Jan 13, 2018)
16-1445210-C-G		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445228-T-G		Osteopetrosis	Uncertain significance (Jan 12, 2018)
16-1445242-T-G		Osteopetrosis	Benign (Jan 13, 2018)
16-1445263-C-T		Osteopetrosis	Uncertain significance (Jan 12, 2018)
16-1445299-G-A		Osteopetrosis	Benign (Jan 13, 2018)
16-1445301-G-A		Osteopetrosis	Uncertain significance (Apr 27, 2017)
16-1445334-A-G		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445338-C-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445342-C-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445383-C-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445416-G-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)
16-1445442-C-T		Osteopetrosis	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN7	protein_coding	protein_coding	ENST00000382745	25	30647

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.272	0.728	125715	0	23	125738	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.11	358	490	0.731	0.0000349	5100
Missense in Polyphen		92	179.97	0.51121		1769
Synonymous	-3.06	283	225	1.26	0.0000185	1649
Loss of Function	4.66	10	43.0	0.232	0.00000224	473

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000178	0.000177
Ashkenazi Jewish	0.000200	0.000198
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000985	0.0000967
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Slowly voltage-gated channel mediating the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the lysosome lumen. {ECO:0000269|PubMed:18449189, ECO:0000269|PubMed:21527911}.
• Disease: DISEASE: Osteopetrosis, autosomal dominant 2 (OPTA2) [MIM:166600]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. It is characterized by sclerosis, predominantly involving the spine, the pelvis and the skull base. {ECO:0000269|PubMed:11741829, ECO:0000269|PubMed:14584882, ECO:0000269|PubMed:19288050, ECO:0000269|PubMed:19953639, ECO:0000269|PubMed:26395888}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. {ECO:0000269|PubMed:26395888}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Recessive Scores

• pRec: 0.298

Intolerance Scores

• loftool: 0.0468
• rvis_EVS: -1.64
• rvis_percentile_EVS: 2.82

Haploinsufficiency Scores

• pHI: 0.238
• hipred: Y
• hipred_score: 0.685
• ghis: 0.625

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.835

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcn7
• Phenotype: pigmentation phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype

Gene ontology

• Biological process: response to pH;chloride transmembrane transport
• Cellular component: nucleoplasm;lysosomal membrane;membrane;integral component of membrane;cytoplasmic vesicle
• Molecular function: voltage-gated chloride channel activity;chloride channel activity;protein binding;ATP binding;antiporter activity