CHD2

protein-coding

chromodomain helicase DNA binding protein 2, the group of DNA helicases|MicroRNA protein coding host genes

Gene summary

The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001271.4

Inheritance

ClinVar variants

P:404U:900B:664

Top phenotype

Develomental and epileptic encephalopathy 94

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr15:92,886,203-93,027,996

External References & Databases

Ensembl (ENSG00000173575)

Transcript & Mutation Effects

hg38 • Region Span ~141.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myoclonic-astatic epilepsySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

developmental and epileptic encephalopathy 94STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014150

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CHD2* variants were first reported in relation to autosomal dominant epileptic encephalopathies in 2013 (PMID:23708187). *CHD2* alters gene expression by affecting chromatin regulation and acetylation. Patients with variants in *CHD2* have been reported to have intellectual disability ranging in severity, autism spectrum disorder, seizures (including generalized myoclonic, atonic, bilateral tonic-clonic, etc.), myoclonus, status epilepticus, and ataxia. The ClinGen Epilepsy GCEP decided to curate variants in this gene for “complex neurodevelopmental disorder” to encompass the variability in severity, age of onset, and clinical presentations. There are 10 unique variants (nonsense, frameshift, splice-site, and missense) reported in 10 probands in 3 publications (PMIDs:23934111, 23708187, 24207121) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by functional alteration of mouse neuronal progenitor cells (PMIDs:25786798). In summary, there is definitive evidence to support the gene-disease relationship between *CHD2* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on July 18, 2018. As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.

developmental and epileptic encephalopathy 94DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014150

Submitter: G2P

Lennox-Gastaut syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016532

Submitter: Orphanet

Clinical Genomic Database (CGD)

Develomental and epileptic encephalopathy 94AD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 23020937

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHD2 variants in ClinVar

38 Conditions Cataloged

Developmental and epileptic encephalopathy 94Total: 1968

not providedTotal: 725

not specifiedTotal: 257

Inborn genetic diseasesTotal: 210

CHD2-related disorderTotal: 95

Intellectual disabilityTotal: 19

Complex neurodevelopmental disorderTotal: 8

EpilepsyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001271.4. 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		2 clinvar	14 clinvar	509 clinvar	5 clinvar	530
missense	13 clinvar	84 clinvar	856 clinvar	144 clinvar	5 clinvar	1102
nonsense	78 clinvar	18 clinvar	6 clinvar			102
start loss			2 clinvar			2
frameshift	121 clinvar	40 clinvar	13 clinvar	1 clinvar		175
splice donor/acceptor (+/-2bp)	16 clinvar	32 clinvar	9 clinvar			57
Total	228	176	900	654	10	1968

Highest pathogenic variant AF is 0.003239837

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001271.4	RefSeq	NP_001262.3	38	MANE Select
ENST00000394196.9	Ensembl	ENSP00000377747.4	38	MANE Select
NM_001042572.3	RefSeq	NP_001036037.1	12	Standard
ENST00000420239.7	Ensembl	ENSP00000406581.2	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
chd2	Danio rerio	Structure: trunk Quality: increased curvature abnormal

Gene / Model

Organism

Observed Phenotype

chd2

Danio rerio

Structure: trunk

Quality: increased curvature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prion disease pathway

Biological Process

chromatin organization
regulation of transcription by RNA polymerase II
muscle organ development
DNA duplex unwinding

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA binding
RNA binding
ATP-dependent DNA helicase activity
protein binding

Cellular Component

nucleus
nucleoplasm
nucleolus
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394196
Coding exons: 38
Length: 144712
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125745
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.21	523	982	0.533	0.0000543	12098
Missense (PolyPhen)		61	273.45	0.22308		3297
Synonymous	0.714	343	360	0.952	0.0000198	3277
Loss of Function	9.50	3	111	0.0270	0.00000633	1308

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	0.000054	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-binding helicase that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3. Involved in myogenesis via interaction with MYOD1: binds to myogenic gene regulatory sequences and mediates incorporation of histone H3.3 prior to the onset of myogenic gene expression, promoting their expression (By similarity). {ECO:0000250}.;
Disease: DISEASE: Epileptic encephalopathy, childhood-onset (EEOC) [MIM:615369]: A severe form of epilepsy characterized by onset of multiple seizure types in the first few years of life and associated with poor prognosis. Affected individuals have cognitive regression and intellectual disability. {ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:25356899}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.0861
RVIS EVS: -1.75
RVIS percentile EVS: 2.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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