CASK

calcium/calmodulin dependent serine protein kinase, the group of PDZ domain containing|Membrane associated guanylate kinases

Basic information

Region (hg38): X:41514934-41923554

Previous symbols: [ "TNRC8" ]

Links

ENSG00000147044 ∙ NCBI:8573 ∙ OMIM:300172 ∙ HGNC:1497 ∙ Uniprot:O14936 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• syndromic X-linked intellectual disability Najm type (Definitive), mode of inheritance: XLD
• FG syndrome 4 (Definitive), mode of inheritance: XLR
• syndromic X-linked intellectual disability Najm type (Definitive), mode of inheritance: XLR
• syndromic X-linked intellectual disability Najm type (Definitive), mode of inheritance: XL
• FG syndrome 4 (Definitive), mode of inheritance: XL
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• syndromic X-linked intellectual disability Najm type (Supportive), mode of inheritance: XL
• syndromic X-linked intellectual disability Najm type (Definitive), mode of inheritance: XL
• FG syndrome 4 (Definitive), mode of inheritance: XL
• FG syndrome 4 (Strong), mode of inheritance: XL
• syndromic X-linked intellectual disability Najm type (Strong), mode of inheritance: XL
• X-linked syndromic intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia; FG syndrome 4; Intellectual developmental disorder, with or without nystagmus	XL	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	12522552; 19165920; 19200522; 19377476; 20029458; 21735175; 21954287

ClinVar

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

• not provided (43 variants)
• Syndromic X-linked intellectual disability Najm type (39 variants)
• Intellectual disability, CASK-related, X-linked (14 variants)
• Inborn genetic diseases (5 variants)
• FG syndrome 4 (2 variants)
• Developmental disorder (2 variants)
• Neurodevelopmental disorder (2 variants)
• Deficiency of butyrylcholinesterase (1 variants)
• Congenital cerebellar hypoplasia (1 variants)
• Syndromic X-linked intellectual disability Najm type;FG syndrome 4 (1 variants)
• CASK-related disorder (1 variants)
• CASK-related intellectual disability and microcephaly with pontine and cerebellar hypoplasia (1 variants)
• FG syndrome 4;Syndromic X-linked intellectual disability Najm type (1 variants)
• Syndromic X-linked intellectual disability Najm type;FG syndrome 4;Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1 variants)
• X-linked syndromic intellectual disability (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASK 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		1	2	109	20	132
missense	4	24	191	9	9	237
nonsense	40	7	1			48
start loss	2					2
frameshift	30	5	1			36
inframe indel	1	1	2			4
splice donor/acceptor (+/-2bp)	17	13	2		1	33
splice region	1	2	23	21	11	58
non coding			16	101	39	156
Total	94	51	215	219	69

Highest pathogenic variant AF is 0.00000902

Variants in CASK

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

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

Position	Type	Phenotype	Significance	ClinVar
X-41519103-C-T			Uncertain significance (Apr 12, 2022)
X-41520420-C-T		Inborn genetic diseases	Likely benign (Jun 29, 2017)
X-41520424-T-C		Intellectual disability, CASK-related, X-linked	Uncertain significance (Aug 03, 2019)
X-41520424-T-TTA			Uncertain significance (Jan 19, 2023)
X-41520434-A-T		Intellectual disability, CASK-related, X-linked	Uncertain significance (Apr 25, 2023)
X-41520444-C-T			Pathogenic (Mar 07, 2018)
X-41520446-A-G		FG syndrome 4	Pathogenic (May 01, 2010)
X-41520447-C-T		Intellectual disability, CASK-related, X-linked	Likely benign (Apr 16, 2022)
X-41520450-T-C		Intellectual disability, CASK-related, X-linked	Likely benign (Jun 23, 2022)
X-41520458-T-C			Uncertain significance (Mar 05, 2020)
X-41520460-C-T		Intellectual disability, CASK-related, X-linked	Uncertain significance (Mar 18, 2022)
X-41520464-C-T			Uncertain significance (May 27, 2022)
X-41520465-G-A		Intellectual disability, CASK-related, X-linked	Benign (Apr 08, 2022)
X-41520467-G-A		Intellectual disability, CASK-related, X-linked • FG syndrome 4 • Syndromic X-linked intellectual disability Najm type	Uncertain significance (May 20, 2023)
X-41520476-C-T			Uncertain significance (Sep 01, 2023)
X-41520483-C-T		Intellectual disability, CASK-related, X-linked	Likely benign (Apr 22, 2023)
X-41520494-T-C			Uncertain significance (Apr 15, 2022)
X-41520505-A-G			Uncertain significance (May 28, 2024)
X-41520510-A-C		Intellectual disability, CASK-related, X-linked • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 10, 2024)
X-41520513-G-A		Intellectual disability, CASK-related, X-linked	Likely benign (Apr 24, 2022)
X-41520515-T-C			Uncertain significance (Nov 07, 2022)
X-41520521-T-C		Intellectual disability, CASK-related, X-linked	Likely benign (Dec 02, 2022)
X-41520521-TTG-T		Syndromic X-linked intellectual disability Najm type	Likely pathogenic (Apr 12, 2023)
X-41520522-T-C		Intellectual disability, CASK-related, X-linked	Likely benign (Aug 27, 2020)
X-41520523-G-T		Global developmental delay	Uncertain significance (Dec 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CASK	protein_coding	protein_coding	ENST00000378166	27	408530

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.97e-7	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.25	133	360	0.370	0.0000274	6089
Missense in Polyphen		36	137.85	0.26115		2260
Synonymous	0.0828	130	131	0.991	0.0000108	1710
Loss of Function	5.93	0	41.0	0.00	0.00000315	669

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1.
• Disease: DISEASE: Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Affected individuals can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus. {ECO:0000269|PubMed:19165920, ECO:0000269|PubMed:19377476}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: FG syndrome 4 (FGS4) [MIM:300422]: FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. {ECO:0000269|PubMed:19200522}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Parkin-Ubiquitin Proteasomal System pathway;Splicing factor NOVA regulated synaptic proteins;Extracellular matrix organization;Neuronal System;Dopamine Neurotransmitter Release Cycle;Neurotransmitter release cycle;Neurexins and neuroligins;Transmission across Chemical Synapses;Syndecan interactions;Non-integrin membrane-ECM interactions;Protein-protein interactions at synapses;Nephrin family interactions;Cell-Cell communication;Syndecan-1-mediated signaling events;Syndecan-2-mediated signaling events;Syndecan-3-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.277

Intolerance Scores

• loftool: 0.0574
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.4

Haploinsufficiency Scores

• pHI: 0.996
• hipred: Y
• hipred_score: 0.775
• ghis: 0.644

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cask
• Phenotype: craniofacial phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); digestive/alimentary 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; vision/eye phenotype; skeleton phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system 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)

Gene ontology

• Biological process: negative regulation of cell-matrix adhesion;protein phosphorylation;cell adhesion;neurotransmitter secretion;negative regulation of keratinocyte proliferation;positive regulation of transcription by RNA polymerase II;GMP metabolic process;GDP metabolic process;negative regulation of wound healing;calcium ion import;positive regulation of calcium ion import;negative regulation of cellular response to growth factor stimulus;regulation of synaptic vesicle exocytosis
• Cellular component: basement membrane;nuclear lamina;nucleolus;cytoplasm;cytosol;plasma membrane;cell-cell junction;focal adhesion;actin cytoskeleton;basolateral plasma membrane;nuclear matrix;vesicle;presynaptic membrane;ciliary membrane;Schaffer collateral - CA1 synapse
• Molecular function: guanylate kinase activity;protein serine/threonine kinase activity;protein binding;calmodulin binding;ATP binding;neurexin family protein binding