GCM2

protein-coding

glial cells missing transcription factor 2

Gene summary

This gene is a homolog of the Drosophila glial cells missing gene, which is thought to act as a binary switch between neuronal and glial cell determination. The protein encoded by this gene contains a conserved N-terminal GCM motif that has DNA-binding activity. The protein is a transcription factor that acts as a master regulator of parathyroid development. It has been suggested that this transcription factor might mediate the effect of calcium on parathyroid hormone expression and secretion in parathyroid cells. Mutations in this gene are associated with hypoparathyroidism. [provided by RefSeq, Jul 2008]

Previous symbols:

GCMB

MANE transcript

NM_004752.4

Inheritance

AD, AR

ClinVar variants

P:24U:168B:64

Top phenotype

Hypoparathyroidism, familial isolated, 2; Hyperparathyroidism 4

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr6:10,873,223-10,882,041

External References & Databases

Ensembl (ENSG00000124827)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperparathyroidism 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024570

Submitter: PanelApp Australia

familial isolated hypoparathyroidism due to agenesis of parathyroid glandSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010618

Submitter: Orphanet

familial isolated hyperparathyroidismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015027

Submitter: Orphanet

hyperparathyroidism 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0024570

Submitter: Labcorp Genetics (formerly Invitae)

hypoparathyroidism, familial isolated, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020798

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hypoparathyroidism, familial isolated, 2; Hyperparathyroidism 4AD/AR

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: In Hypoparathyroidism, familial isolated, early recognition of electrolyte abnormalitities (eg, hypocalcemia) can allow prompt treatment in order to avoid severe sequelae; In Hyperparathyroidism 4, individuals have been described with multiple parathyroid tumors (as well as other neoplasms), and awareness may allow early diagnosis and management of these tumors and sequelae

Refs: 15863676; 18583467; 19940031; 20190276; 20463099; 22066718; 23155703; 27745835

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GCM2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 147

Hypoparathyroidism, familial isolated, 2Total: 93

Hyperparathyroidism 4Total: 82

Inborn genetic diseasesTotal: 54

GCM2-related disorderTotal: 39

Familial hypoparathyroidismTotal: 38

not specifiedTotal: 34

Familial hyperparathyroidism or Hypocalciuric hypercalcaemiaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004752.4. 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			9 clinvar	48 clinvar	1 clinvar	58
missense	1 clinvar	8 clinvar	152 clinvar	14 clinvar	1 clinvar	176
nonsense	3 clinvar	5 clinvar				8
start loss		1 clinvar	1 clinvar			2
frameshift	3 clinvar	2 clinvar	5 clinvar			10
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	7	17	168	62	2	256

Highest pathogenic variant AF is 0.000087348366

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004752.4	RefSeq	NP_004743.1	5	MANE Select
ENST00000379491.5	Ensembl	ENSP00000368805.4	5	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gcm2	Danio rerio	Structure: neuromast hair cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

gcm2

Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

transcription by RNA polymerase II
cellular calcium ion homeostasis
multicellular organism development
cellular phosphate ion homeostasis
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
sequence-specific DNA binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379491
Coding exons: 5
Length: 8719
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.676	246	278	0.886	0.0000159	3330
Missense (PolyPhen)		57	80.814	0.70532		925
Synonymous	0.345	103	108	0.958	0.00000676	986
Loss of Function	2.21	8	18.1	0.441	0.00000103	201

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that binds specific sequences on gene promoters and activate their transcription. Through the regulation of gene transcription, may play a role in parathyroid gland development. {ECO:0000269|PubMed:20190276, ECO:0000269|PubMed:27745835, ECO:0000269|PubMed:9928992}.;
Disease: DISEASE: Hypoparathyroidism, familial isolated (FIH) [MIM:146200]: A disorder characterized by hypocalcemia and hyperphosphatemia due to inadequate secretion of parathyroid hormone. Clinical features include seizures, tetany and cramps. {ECO:0000269|PubMed:15728199, ECO:0000269|PubMed:15863676, ECO:0000269|PubMed:20190276, ECO:0000269|PubMed:20463099, ECO:0000269|PubMed:23155703, ECO:0000269|Ref.3}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperparathyroidism 4 (HRPT4) [MIM:617343]: A form of familial primary hyperparathyroidism, an hypercalcemic disorder caused by inappropriate oversecretion of parathyroid hormone due to parathyroid hyperplasia or neoplasms. Clinical features include hypercalcemia, phosphaturia, and increased bone resorption. HRPT4 inheritance is autosomal dominant. {ECO:0000269|PubMed:27745835}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.589
RVIS EVS: 1.16
RVIS percentile EVS: 92.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0999

Gene Damage Prediction

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