TUBGCP6

protein-coding

tubulin gamma complex associated protein 6, the group of Tubulin gamma complex associated protein family

Gene summary

The protein encoded by this gene is part of a large multisubunit complex required for microtubule nucleation at the centrosome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_020461.4

Inheritance

ClinVar variants

P:149U:993B:781

Top phenotype

Microcephaly and chorioretinopathy, autosomal recessive 1

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr22:50,217,689-50,245,023

External References & Databases

Ensembl (ENSG00000128159)

Transcript & Mutation Effects

hg38 • Region Span ~27.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly and chorioretinopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly and chorioretinopathy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: G2P

microcephaly and chorioretinopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: PanelApp Australia

microcephaly and chorioretinopathy 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: Orphanet

microcephaly and chorioretinopathy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: ClinGen

TUBGCP6 was first reported in relation to autosomal recessive microcephaly and chorioretinopathy 1 in 2012 (Puffenberger et al., 2012; PMID: 22279524). An important note is that this condition, which has both microcephaly and the ophthalmic/retinal phenotype, is distinct from simple microcephaly. No pre-curation was necessary for the gene as there is only one gene disease assertion for autosomal recessive microcephaly and chorioretinopathy 1 (OMIM: # 251270). 12 variants (missense, in-frame duplication, read-through, splice site, frameshift, and nonsense) that have been reported in 7 probands in 3 publications (PMIDs: 22279524, 25344692, 37031378) are included in this curation. The maximum score for genetic evidence has been reached. There is only one reported prenatal diagnosis of this condition, described by Thomas-Wilson et al., 2023 (PMID: 37031378), and found by fetal ultrasound/MRI exams showing microcephaly. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence (expression evidence, biochemical function, functional alteration; PMIDs: 19861490, 31874114). The deletion of the gene has been shown to cause cell division defects, consistent with short stature/developmental issues, often seen in affected individuals. In summary, there is definitive evidence supporting the relationship between TUBGCP6 and autosomal recessive chorioretinopathy and microcephaly 1. 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 Prenatal GCEP on the meeting date [May 31, 2023] (SOP Version 1).

Clinical Genomic Database (CGD)

Microcephaly and chorioretinopathy, autosomal recessive 1AR

Manifestation: Neurologic; Ophthalmologic

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: 5936364; 22279524; 25344692

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBGCP6 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 2072

Inborn genetic diseasesTotal: 416

not specifiedTotal: 342

TUBGCP6-related disorderTotal: 103

Microcephaly and chorioretinopathy 1Total: 92

Retinal dystrophyTotal: 18

Microcephaly and chorioretinopathy with or without intellectual disabilityTotal: 2

Optic atrophyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020461.4. 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			10 clinvar	679 clinvar	4 clinvar	693
missense	1 clinvar	3 clinvar	971 clinvar	94 clinvar	4 clinvar	1073
nonsense	25 clinvar	16 clinvar	4 clinvar			45
start loss						0
frameshift	50 clinvar	30 clinvar	6 clinvar			86
splice donor/acceptor (+/-2bp)	3 clinvar	21 clinvar	2 clinvar			26
Total	79	70	993	773	8	1923

Highest pathogenic variant AF is 0.0000893308

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020461.4	RefSeq	NP_065194.3	25	MANE Select
ENST00000248846.10	Ensembl	ENSP00000248846.5	25	MANE Select
ENST00000425018.1	Ensembl	ENSP00000405979.1	10	Standard
ENST00000434349.1	Ensembl	ENSP00000409650.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Recruitment of mitotic centrosome proteins and complexes
Centrosome maturation
G2/M Transition
Mitotic G2-G2/M phases
Recruitment of NuMA to mitotic centrosomes

Biological Process

mitotic cell cycle
microtubule nucleation
cytoplasmic microtubule organization
spindle assembly
meiotic cell cycle

Molecular Function

microtubule binding
gamma-tubulin binding
microtubule minus-end binding

Cellular Component

spindle pole
equatorial microtubule organizing center
gamma-tubulin complex
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000248846
Coding exons: 25
Length: 27304
Individuals with no LoFs: 125455
Homozygous LoFs: 0
Heterozygous LoFs: 293
Defined: 125748
p: 0.00117

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.944	1215	1.13e+3	1.08	0.0000745	11690
Missense (PolyPhen)		438	417.76	1.0484		4608
Synonymous	-4.14	619	501	1.24	0.0000370	3765
Loss of Function	2.10	59	79.2	0.745	0.00000407	847

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00084	0.00081	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.0010	0.0010	notable
Finnish	0.0020	0.0020	notable
European (Non-Finnish)	0.0013	0.0012	notable
South Asian	0.0011	0.0011	notable
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome. {ECO:0000269|PubMed:11694571}.;
Disease: DISEASE: Microcephaly and chorioretinopathy, autosomal recessive, 1 (MCCRP1) [MIM:251270]: A syndrome characterized by microcephaly, cognitive impairment, underdeveloped retina and choroid, and epilepsy in some patients. The more anterior parts of the retina, near the periphery and pars plana, have a grayish hue and diminutive vasculature similar to retinopathy of prematurity. Visual impairment becomes evident during the first year of life. {ECO:0000269|PubMed:22279524}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.892
RVIS EVS: -2.6
RVIS percentile EVS: 0.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.135

Gene Damage Prediction

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