MCPH1

protein-coding

microcephalin 1

Gene summary

This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MANE transcript

NM_024596.5

Inheritance

ClinVar variants

P:131U:334B:410

Top phenotype

Microcephaly, primary autosomal recessive, 1

gnomAD constraint

pLI —, LoF o/e 1.11

Max pathogenic AF

—

Genomic locus

chr8:6,406,592-6,648,508

External References & Databases

Ensembl (ENSG00000147316)

Transcript & Mutation Effects

hg38 • Region Span ~241.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial ovarian cancerNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

microcephaly 1, primary, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009617

Submitter: G2P

microcephaly with intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100200

Submitter: ClinGen

Variants in *MCPH1* were first reported in relation to autosomal recessive microcephaly with intellectual disability in 2010 (PMID: 20978018). Probands are characterized by microcephaly with mild to moderate intellectual disability or developmental delay, and dysmorphic features including up-slanting palpebral fissure and broad tip nose (PMIDs: 22855649, 25870538, 20978018). Nineteen unique homozygous or compound loss-of-function variants, reported in multiple unrelated probands, in five publications, are included in this curation (PMIDs: 20978018, 25870538, 22855649, 35281599, 35456400). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for the disease is reported as haploinsufficiency. Currently, the gene-disease relationship is not supported by experimental evidence. Mouse models recapitulating microcephaly are described but were not scored as no developmental delay phenotype was described (PMID: 33542216). In summary, there is definitive evidence to support the relationship between MCPH1 and autosomal recessive microcephaly with 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 January 17, 2023 (SOP 9).

hereditary breast carcinomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0016419

Submitter: ClinGen

microcephaly 1, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009617

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly with intellectual disabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100200

Submitter: PanelApp Australia

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly, primary autosomal recessive, 1AR

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

Refs: 7693575; 12046007; 11857108; 15199523; 16311745; 20978018; 20101680; 21668957

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCPH1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 904

Microcephaly 1, primary, autosomal recessiveTotal: 222

Inborn genetic diseasesTotal: 205

not specifiedTotal: 155

MCPH1-related disorderTotal: 55

Autosomal recessive primary microcephalyTotal: 14

Intellectual disabilityTotal: 6

Lymphatic malformation 10Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024596.5. 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	352 clinvar	3 clinvar	356
missense	1 clinvar	8 clinvar	317 clinvar	47 clinvar	6 clinvar	379
nonsense	20 clinvar	26 clinvar	5 clinvar	1 clinvar		52
start loss						0
frameshift	16 clinvar	29 clinvar	4 clinvar			49
splice donor/acceptor (+/-2bp)	3 clinvar	28 clinvar	7 clinvar	1 clinvar		39
Total	40	91	334	401	9	875

Highest pathogenic variant AF is 0.00022070402

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024596.5	RefSeq	NP_078872.3	14	MANE Select
ENST00000344683.10	Ensembl	ENSP00000342924.5	14	MANE Select
NM_001172574.2	RefSeq	NP_001166045.2	8	Standard
NM_001172575.2	RefSeq	NP_001166046.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Condensation of Prophase Chromosomes
Mitotic Prophase
M Phase
Cell Cycle
Cell Cycle, Mitotic

Biological Process

negative regulation of transcription by RNA polymerase II
establishment of mitotic spindle orientation
cerebral cortex development
regulation of kinase activity
regulation of centrosome cycle

Molecular Function

protein binding
identical protein binding

Cellular Component

nucleoplasm
cytoplasm
microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000344683
Coding exons: 14
Length: 237032
Individuals with no LoFs: 124661
Homozygous LoFs: 0
Heterozygous LoFs: 151
Defined: 124812
p: 0.000605

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-4.76	736	451	1.63	0.0000248	5469
Missense (PolyPhen)		312	196.12	1.5909		2491
Synonymous	-5.87	273	174	1.56	0.0000107	1575
Loss of Function	-0.651	42	37.7	1.11	0.00000178	507

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00032	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0018	0.0018	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00074	0.00074	rare
South Asian	0.00033	0.00033	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex. {ECO:0000269|PubMed:12046007, ECO:0000269|PubMed:15199523, ECO:0000269|PubMed:15220350}.;
Disease: DISEASE: Microcephaly 1, primary, autosomal recessive (MCPH1) [MIM:251200]: A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals are mentally retarded. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. Some MCHP1 patients also present growth retardation, short stature, and misregulated chromosome condensation as indicated by a high number of prophase-like cells detected in routine cytogenetic preparations and poor-quality metaphase G-banding. {ECO:0000269|PubMed:12046007, ECO:0000269|PubMed:15199523, ECO:0000269|PubMed:16211557}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 1.00

Intolerance Scores

LoFtool: 0.742
RVIS EVS: 1.39
RVIS percentile EVS: 94.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.382

Gene Damage Prediction

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