MLC1

modulator of VRAC current 1

Basic information

Region (hg38): 22:50059390-50085426

Links

ENSG00000100427 ∙ NCBI:23209 ∙ OMIM:605908 ∙ HGNC:17082 ∙ Uniprot:Q15049 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• megalencephalic leukoencephalopathy with subcortical cysts 1 (Definitive), mode of inheritance: AR
• megalencephalic leukoencephalopathy with subcortical cysts 1 (Definitive), mode of inheritance: AR
• megalencephalic leukoencephalopathy with subcortical cysts 1 (Definitive), mode of inheritance: AR
• megalencephalic leukoencephalopathy with subcortical cysts (Supportive), mode of inheritance: AD
• megalencephalic leukoencephalopathy with subcortical cysts 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Megalencephalic leukoencephalopathy with subcortical cysts 1	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	11254442; 12939431; 18757878; 20301707; 20560255; 21145992; 21160490; 21487377; 22416245; 22552818; 24824219

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MLC1 gene.

• not provided (408 variants)
• Megalencephalic leukoencephalopathy with subcortical cysts 1 (249 variants)
• Megalencephalic leukoencephalopathy with subcortical cysts (59 variants)
• not specified (25 variants)
• Inborn genetic diseases (10 variants)
• Abnormality of the nervous system (1 variants)
• MLC1-related condition (1 variants)
• CNS demyelination;Cerebellar ataxia;Macrocephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MLC1 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			2	131	5	138
missense	4	21	76	6	4	111
nonsense	3	16				19
start loss						0
frameshift	18	18	2			38
inframe indel			6	1		7
splice donor/acceptor (+/-2bp)	2	22	3			27
splice region			4	21	1	26
non coding		1	48	52	75	176
Total	27	78	137	190	84

Highest pathogenic variant AF is 0.0000131

Variants in MLC1

This is a list of pathogenic ClinVar variants found in the MLC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-50059416-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059420-A-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059508-T-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059515-G-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059532-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Likely benign (Jan 13, 2018)
22-50059534-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 12, 2018)
22-50059601-G-GC		Megalencephalic leukoencephalopathy with subcortical cysts	Likely benign (Jun 14, 2016)
22-50059620-G-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 13, 2018)
22-50059632-T-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059649-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50059709-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 12, 2018)
22-50059747-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 13, 2018)
22-50059796-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 12, 2018)
22-50059802-G-A		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Apr 27, 2017)
22-50059810-C-G		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Mar 01, 2023)
22-50059819-C-A		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 12, 2018)
22-50059894-A-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Likely benign (Jan 12, 2018)
22-50059960-C-A		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 13, 2018)
22-50060084-G-A		Megalencephalic leukoencephalopathy with subcortical cysts 1	Likely benign (Apr 01, 2023)
22-50060090-T-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)
22-50060185-T-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 12, 2018)
22-50060214-A-AT		Megalencephalic leukoencephalopathy with subcortical cysts	Likely benign (Jun 14, 2016)
22-50060249-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 13, 2018)
22-50060262-T-C		Megalencephalic leukoencephalopathy with subcortical cysts 1	Benign (Jan 12, 2018)
22-50060277-C-T		Megalencephalic leukoencephalopathy with subcortical cysts 1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MLC1	protein_coding	protein_coding	ENST00000311597	11	26512

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.24e-8	0.538	125705	1	42	125748	0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.203	210	218	0.961	0.0000150	2409
Missense in Polyphen		114	110.19	1.0346		1273
Synonymous	0.415	96	101	0.948	0.00000820	785
Loss of Function	1.03	14	18.8	0.744	0.00000104	214

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000292	0.000275
Ashkenazi Jewish	0.00	0.00
East Asian	0.000220	0.000217
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.000188	0.000176
Middle Eastern	0.000220	0.000217
South Asian	0.000327	0.000327
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx. {ECO:0000269|PubMed:22328087}.
• Pathway: erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;integrin signaling pathway;mcalpain and friends in cell motility (Consensus)

Recessive Scores

• pRec: 0.206

Intolerance Scores

• loftool: 0.0931
• rvis_EVS: 0
• rvis_percentile_EVS: 53.85

Haploinsufficiency Scores

• pHI: 0.318
• hipred: N
• hipred_score: 0.251
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.793

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mlc1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: mlc1
• Affected structure: midbrain
• Phenotype tag: abnormal
• Phenotype quality: physical object quality

Gene ontology

• Biological process: ion transport;protein transport;vesicle-mediated transport;positive regulation of intracellular transport;regulation of response to osmotic stress;protein complex oligomerization;cellular response to cholesterol;caveolin-mediated endocytosis
• Cellular component: cytoplasm;lysosome;endosome;early endosome;endoplasmic reticulum;plasma membrane;caveola;cell-cell junction;integral component of membrane;basolateral plasma membrane;apical plasma membrane;clathrin-coated vesicle;cytoplasmic vesicle;membrane raft;perinuclear region of cytoplasm;recycling endosome
• Molecular function: protein binding;protein transporter activity;protein-containing complex binding