CASK

protein-coding

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

Gene summary

This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Previous symbols:

TNRC8

MANE transcript

NM_001367721.1

Inheritance

XL, AD

ClinVar variants

P:215U:416B:227

Top phenotype

Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia; FG syndrome 4; Intellectual developmental disorder, with or without nystagmus

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:41,514,934-41,923,554

External References & Databases

Ensembl (ENSG00000147044)

Transcript & Mutation Effects

hg38 • Region Span ~408.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

FG syndrome 4DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010318

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

FG syndrome 4STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010318

Submitter: Labcorp Genetics (formerly Invitae)

syndromic X-linked intellectual disability Najm typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010417

Submitter: Orphanet

syndromic X-linked intellectual disability Najm typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010417

Submitter: Labcorp Genetics (formerly Invitae)

X-linked syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0020119

Submitter: ClinGen

*CASK*, which encodes a synaptic scaffolding protein, was first reported in relation to X-linked syndromic intellectual disability in 2008 (Najm et al., PMID: 19165920). Sixteen variants (nonsense, splice, frameshift, start loss, missense) that have been reported in 18 probands in four publications (PMIDs: 19165920, 21735175, 21954287, 25886057) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Some cases could not be scored because the deletions were larger than 10 kb (see Moog et al., 2011, PMID: 21954287, and Moog et al., 2015, PMID: 25886057). This gene-disease relationship is also supported by mouse models that recapitulate the phenotype in humans. In summary, there is definitive evidence supporting the relationship between *CASK* and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 9, 2019 (SOP Version 6).

syndromic X-linked intellectual disability Najm typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010417

Submitter: G2P

FG syndrome 4DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010318

Submitter: G2P

syndromic X-linked intellectual disability Najm typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010417

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia; FG syndrome 4; Intellectual developmental disorder, with or without nystagmusXL

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 12522552; 19165920; 19200522; 19377476; 20029458; 21735175; 21954287

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASK variants in ClinVar

29 Conditions Cataloged

Intellectual disability, CASK-related, X-linkedTotal: 561

not providedTotal: 355

Syndromic X-linked intellectual disability Najm typeTotal: 142

not specifiedTotal: 132

Inborn genetic diseasesTotal: 80

FG syndrome 4Total: 51

CASK-related disorderTotal: 47

Intellectual disabilityTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367721.1. 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	17 clinvar	161 clinvar	19 clinvar	199
missense	7 clinvar	35 clinvar	353 clinvar	37 clinvar	9 clinvar	441
nonsense	43 clinvar	13 clinvar	8 clinvar			64
start loss	2 clinvar		1 clinvar			3
frameshift	37 clinvar	28 clinvar	2 clinvar			67
splice donor/acceptor (+/-2bp)	20 clinvar	28 clinvar	35 clinvar		1 clinvar	84
Total	110	105	416	198	29	858

Highest pathogenic variant AF is 0.0000018603024

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367721.1	RefSeq	NP_001354650.1	27	MANE Select
ENST00000378163.7	Ensembl	ENSP00000367405.1	27	MANE Select
NM_001126054.3	RefSeq	NP_001119526.1	26	Standard
NM_001126055.3	RefSeq	NP_001119527.1	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Parkin-Ubiquitin Proteasomal System pathway
Splicing factor NOVA regulated synaptic proteins
Extracellular matrix organization
Neuronal System
Dopamine Neurotransmitter Release Cycle

Biological Process

negative regulation of cell-matrix adhesion
protein phosphorylation
cell adhesion
neurotransmitter secretion
negative regulation of keratinocyte proliferation

Molecular Function

guanylate kinase activity
protein serine/threonine kinase activity
protein binding
calmodulin binding
ATP binding

Cellular Component

basement membrane
nuclear lamina
nucleolus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378166
Coding exons: 27
Length: 408530
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	4.25	133	360	0.370	0.0000274	6089
Missense (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

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: 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.;

Recessive Scores

pRec: 0.277

Intolerance Scores

LoFtool: 0.0574
RVIS EVS: -0.71
RVIS percentile EVS: 14.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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