CHD8

chromodomain helicase DNA binding protein 8, the group of Small nucleolar RNA protein coding host genes

Basic information

Region (hg38): 14:21385193-21456126

Previous symbols: [ "HELSNF1" ]

Links

ENSG00000100888 ∙ NCBI:57680 ∙ OMIM:610528 ∙ HGNC:20153 ∙ Uniprot:Q9HCK8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autism (Strong), mode of inheritance: AD
• intellectual disability (Strong), mode of inheritance: AD
• congenital myasthenic syndrome (Limited), mode of inheritance: AD
• intellectual developmental disorder with autism and macrocephaly (Strong), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder with autism and macrocephaly	AD	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	Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic	21572417; 22495306; 22495309; 22495311; 22521361; 23160955; 24998929; 31001818

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CHD8 gene.

• not provided (812 variants)
• Inborn genetic diseases (236 variants)
• Intellectual developmental disorder with autism and macrocephaly (123 variants)
• not specified (22 variants)
• CHD8-related condition (17 variants)
• Autism spectrum disorder (14 variants)
• Neurodevelopmental disorder (7 variants)
• See cases (5 variants)
• Intellectual disability (5 variants)
• CHD8-Related Disorders (4 variants)
• Developmental disorder (2 variants)
• Autism;Intellectual disability (2 variants)
• Fatigable weakness;Increased muscle fatiguability;Macrocephaly;Overgrowth;Congenital ptosis (1 variants)
• Neurodevelopmental delay (1 variants)
• CHD8-Related Disorder (1 variants)
• Autism (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)
• CHD8-associated Neurodevelopmental syndrome (1 variants)
• Autism spectrum disorder;Intellectual disability (1 variants)
• Macrocephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CHD8 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			7	140	12	159
missense	3	14	444	31	3	495
nonsense	39	15				54
start loss			1			1
frameshift	41	13	1			55
inframe indel			15	2		17
splice donor/acceptor (+/-2bp)	7	14	3			24
splice region		1	18	17	1	37
non coding			6	89	62	157
Total	90	56	477	262	77

Highest pathogenic variant AF is 0.00000658

Variants in CHD8

This is a list of pathogenic ClinVar variants found in the CHD8 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-21385465-G-A			Likely benign (Feb 06, 2020)
14-21385470-AT-A			Benign (Aug 20, 2019)
14-21385614-C-CA			Uncertain significance (Nov 08, 2022)
14-21385626-T-C		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
14-21385635-G-A		Intellectual developmental disorder with autism and macrocephaly	Uncertain significance (Jan 27, 2023)
14-21385639-C-T			Uncertain significance (Jan 22, 2021)
14-21385651-G-T			Uncertain significance (Sep 02, 2022)
14-21385683-C-T			Uncertain significance (Feb 06, 2022)
14-21385684-T-C		Inborn genetic diseases	Uncertain significance (Dec 27, 2017)
14-21385694-A-G		Inborn genetic diseases	Benign (Jan 30, 2024)
14-21385697-A-G			Likely benign (Jul 22, 2023)
14-21385698-T-A		CHD8-related disorder	Uncertain significance (Jan 01, 2024)
14-21385709-T-A			Uncertain significance (Oct 25, 2022)
14-21385712-GTCA-G		Autism spectrum disorder	Likely benign (-)
14-21385715-A-G		not specified	Likely benign (Mar 04, 2024)
14-21385721-ATCT-A			Uncertain significance (Dec 18, 2023)
14-21385727-T-C			Likely benign (Jan 06, 2022)
14-21385727-T-TTCATCCTCATCG		Intellectual developmental disorder with autism and macrocephaly	Uncertain significance (Jan 23, 2024)
14-21385738-C-T		Inborn genetic diseases	Uncertain significance (Jan 05, 2019)
14-21385739-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 13, 2024)
14-21385752-G-A			Uncertain significance (Apr 12, 2023)
14-21385754-T-C			Likely benign (Sep 12, 2022)
14-21385757-C-T			Likely benign (Oct 01, 2023)
14-21385759-G-T			Uncertain significance (Jan 08, 2024)
14-21385769-C-T			Likely benign (May 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CHD8	protein_coding	protein_coding	ENST00000399982	37	70933

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	7.62e-18	124641	0	12	124653	0.0000481

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.95	806	1.44e+3	0.559	0.0000827	16853
Missense in Polyphen		166	516.11	0.32164		5933
Synonymous	1.03	473	502	0.941	0.0000254	5048
Loss of Function	10.1	5	129	0.0388	0.00000800	1415

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000154	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000556	0.0000556
Finnish	0.0000465	0.0000464
European (Non-Finnish)	0.0000267	0.0000265
Middle Eastern	0.0000556	0.0000556
South Asian	0.0000984	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: DNA helicase that acts as a chromatin remodeling factor and regulates transcription. Acts as a transcription repressor by remodeling chromatin structure and recruiting histone H1 to target genes. Suppresses p53/TP53-mediated apoptosis by recruiting histone H1 and preventing p53/TP53 transactivation activity. Acts as a negative regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) activity. Negatively regulates CTNNB1- targeted gene expression by being recruited specifically to the promoter regions of several CTNNB1 responsive genes. Involved in both enhancer blocking and epigenetic remodeling at chromatin boundary via its interaction with CTCF. Acts as a suppressor of STAT3 activity by suppressing the LIF-induced STAT3 transcriptional activity. Also acts as a transcription activator via its interaction with ZNF143 by participating in efficient U6 RNA polymerase III transcription. {ECO:0000255|HAMAP- Rule:MF_03071, ECO:0000269|PubMed:17938208, ECO:0000269|PubMed:18378692}.
• Disease: DISEASE: Autism 18 (AUTS18) [MIM:615032]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. {ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:26637798}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Wnt signaling pathway - Homo sapiens (human);Wnt Signaling Pathway;Signaling by WNT;Signal Transduction;Deactivation of the beta-catenin transactivating complex;Regulation of nuclear beta catenin signaling and target gene transcription;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.120

Intolerance Scores

• loftool: 0.121
• rvis_EVS: -2.34
• rvis_percentile_EVS: 1.18

Haploinsufficiency Scores

• pHI: 0.711
• hipred: Y
• hipred_score: 0.785
• ghis: 0.621

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.948

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Chd8
• Phenotype: growth/size/body region phenotype; cellular 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); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms 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)

Zebrafish Information Network

• Gene name: chd8
• Affected structure: enteric neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;in utero embryonic development;brain development;Wnt signaling pathway;DNA duplex unwinding;social behavior;ATP-dependent chromatin remodeling;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of transcription by RNA polymerase III;digestive tract development;prepulse inhibition;negative regulation of canonical Wnt signaling pathway;negative regulation of fibroblast apoptotic process
• Cellular component: nucleus;nucleoplasm;protein-containing complex;MLL1 complex
• Molecular function: p53 binding;DNA binding;DNA helicase activity;chromatin binding;protein binding;ATP binding;beta-catenin binding;DNA-dependent ATPase activity;methylated histone binding;histone binding;armadillo repeat domain binding