MCPH1

microcephalin 1

Basic information

Region (hg38): 8:6406592-6648508

Links

ENSG00000147316 ∙ NCBI:79648 ∙ OMIM:607117 ∙ HGNC:6954 ∙ Uniprot:Q8NEM0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephaly 1, primary, autosomal recessive (Definitive), mode of inheritance: AR
• autosomal recessive primary microcephaly (Supportive), mode of inheritance: AR
• microcephaly 1, primary, autosomal recessive (Strong), mode of inheritance: AR
• hereditary breast carcinoma (Limited), mode of inheritance: AD
• familial ovarian cancer (No Known Disease Relationship), mode of inheritance: AD
• microcephaly with intellectual disability (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly, primary autosomal recessive, 1	AR	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	Neurologic	7693575; 12046007; 11857108; 15199523; 16311745; 20978018; 20101680; 21668957

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCPH1 gene.

• not provided (29 variants)
• Microcephaly 1, primary, autosomal recessive (9 variants)
• Autosomal recessive primary microcephaly (5 variants)
• See cases (2 variants)
• Bartter syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCPH1 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				294	9	303
missense	1	4	223	15	14	257
nonsense	16	4	2			22
start loss						0
frameshift	18	6	3			27
inframe indel			3			3
splice donor/acceptor (+/-2bp)	3	12	2	1		18
splice region			8	35		43
non coding			41	180	67	288
Total	38	26	274	490	90

Highest pathogenic variant AF is 0.000118

Variants in MCPH1

This is a list of pathogenic ClinVar variants found in the MCPH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-6406609-G-C		Primary Microcephaly, Recessive	Benign (Jun 16, 2018)
8-6406627-A-C		Microcephaly 1, primary, autosomal recessive	Uncertain significance (Jan 13, 2018)
8-6406629-G-A		Microcephaly 1, primary, autosomal recessive	Uncertain significance (Apr 27, 2017)
8-6406658-G-C			Uncertain significance (May 18, 2018)
8-6406660-C-T		MCPH1-related disorder	Likely benign (Oct 14, 2020)
8-6406663-C-G		MCPH1-related disorder	Likely benign (Apr 26, 2019)
8-6406672-C-T			Uncertain significance (Oct 10, 2021)
8-6406673-G-A			Likely benign (Jul 08, 2023)
8-6406674-G-T			Uncertain significance (Aug 24, 2023)
8-6406676-C-G			Likely benign (Dec 04, 2023)
8-6406676-C-T			Benign/Likely benign (Jan 18, 2024)
8-6406682-C-T			Likely benign (Dec 30, 2023)
8-6406685-G-A			Likely benign (Nov 25, 2023)
8-6406685-G-C			Likely benign (Feb 14, 2023)
8-6406689-G-A			Uncertain significance (May 04, 2022)
8-6406690-GTGA-G		Microcephaly 1, primary, autosomal recessive	Pathogenic (May 04, 2016)
8-6406691-T-C			Likely pathogenic (Jan 07, 2024)
8-6406697-A-G			Likely benign (Feb 03, 2023)
8-6406699-T-C			Likely benign (Aug 28, 2023)
8-6406701-C-T			Likely benign (Jan 20, 2024)
8-6406702-C-T			Likely benign (Jul 17, 2023)
8-6406707-G-A			Likely benign (Jan 24, 2024)
8-6406708-C-T			Likely benign (Dec 16, 2022)
8-6406744-C-G			Likely benign (Apr 16, 2019)
8-6408449-TAGCCTCAAGCAATCCTCCCGCCTCCACCTTGCAAAATGCTGGGATTACAGGCATGAGCTACTTTGTTCAGCCAGTAGAAGAAACTTCATTTACTTTTCTTATTTTTGAGGCAAGGTCTTTCTCTGCTGCCCAGGCTGGAGTGCAATGGTGCGATCATAACTCAGCTTCTACCTCCTGGGCTCTAGGGATTCTCCCACCTCAGCTTCTCCACCCTACCCACCCCCATTTCCCACCCAGTAGCTGGGACTACAGCCACTCGCCACCATTCCTGGCTAATTAAAAACAAAATTTTTTTTAGAGACAGGGTTTCACTATGTTGCCCAGGCTGGTCTCAAACTTCTGTGCCCAAGTGATCCCACTGCCTTGGCCTTCCAGAGTGCTGCAATTACAGCATGAGCCACCACACCTGGCCAGTAGAGTAAATTTTTGTTTTACTTTTTTCTTTTTTTTTTTTTGAAACGGGTCTCGCCCTGTCACCCAGGCTGGAGTGCAATGGCGCAATCTCGGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAGTAGCTGGGATTACAGGTGCCCGCCACCATGCTCGGCTAATTTTTTGTATCTTTTAGTAGAGATGGTTTTTCACCATGTTGGCCCGGCTGGTCTCAAACCCCTGACTTCGTGGATCCACCCACTTCCGCCTCCCACAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCGGCCTCGGTTTACTCTTAAATGTAAATAGAACAAAATCTATTGGGCAGGGGATGCTGGAATTTCAAATGTATGTTTCATGTTCATATCTTGTTTTCAGATGTAG-T			Likely pathogenic (Jan 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCPH1	protein_coding	protein_coding	ENST00000344683	14	237032

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.76e-30	0.0000126	124661	0	151	124812	0.000605

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-4.76	736	451	1.63	0.0000248	5469
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000764	0.000763
Ashkenazi Jewish	0.00	0.00
East Asian	0.00184	0.00184
Finnish	0.0000464	0.0000464
European (Non-Finnish)	0.000744	0.000742
Middle Eastern	0.00184	0.00184
South Asian	0.000327	0.000327
Other	0.000495	0.000495

dbNSFP

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.
• Pathway: Condensation of Prophase Chromosomes;Mitotic Prophase;M Phase;Cell Cycle;Cell Cycle, Mitotic (Consensus)

Recessive Scores

• pRec: 1.00

Intolerance Scores

• loftool: 0.742
• rvis_EVS: 1.39
• rvis_percentile_EVS: 94.66

Haploinsufficiency Scores

• pHI: 0.0779
• hipred: Y
• hipred_score: 0.518
• ghis: 0.464

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: N
• gene_indispensability_score: 0.382

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mcph1
• Phenotype: cellular phenotype; homeostasis/metabolism 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; pigmentation 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); hearing/vestibular/ear phenotype; vision/eye phenotype; immune system phenotype; skeleton 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); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Gene ontology

• 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;regulation of inflammatory response;bone development;regulation of chromosome condensation;protein localization to centrosome;mitotic cell cycle arrest;neuronal stem cell population maintenance
• Cellular component: nucleoplasm;cytoplasm;microtubule organizing center
• Molecular function: protein binding;identical protein binding