GPHN

gephyrin

Basic information

Region (hg38): 14:66507407-67181803

Links

ENSG00000171723 ∙ NCBI:10243 ∙ OMIM:603930 ∙ HGNC:15465 ∙ Uniprot:Q9NQX3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (Moderate), mode of inheritance: AR
• hereditary hyperekplexia (Supportive), mode of inheritance: AD
• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (Limited), mode of inheritance: AR
• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (Moderate), mode of inheritance: AR
• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperekplexia, autosomal dominant; Molybdenum cofactor deficiency, type C	AD/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	Biochemical; Musculoskeletal; Neurologic; Ophthalmologic	11095995; 12684523; 20301437; 21031595; 22040219
In Hyperekplexia, autosomal dominant, evidence for pathogenicity is unclear (though multiple medical treatments, including clonazepam may be beneficial)

ClinVar

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

• Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C (20 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GPHN 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				148	1	149
missense	2		258	5		265
nonsense	9		2			11
start loss						0
frameshift	9	1	1			11
inframe indel			3			3
splice donor/acceptor (+/-2bp)		15	1			16
splice region			31	35	3	69
non coding			7	122	36	165
Total	20	16	272	275	37

Highest pathogenic variant AF is 0.0000131

Variants in GPHN

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

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

Position	Type	Phenotype	Significance	ClinVar
14-66508527-C-T			Uncertain significance (Jan 29, 2019)
14-66508533-G-T		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Nov 10, 2023)
14-66508536-C-T		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jun 06, 2021)
14-66508539-G-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Sep 26, 2022)
14-66508547-T-C		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Sep 30, 2023)
14-66508547-T-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Dec 12, 2023)
14-66508552-A-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C • Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
14-66508553-C-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Jun 02, 2022)
14-66508553-C-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A • Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C • GPHN-related disorder	Benign/Likely benign (Jan 27, 2024)
14-66508555-A-T		Hyperekplexia • Hyperekplexia 1 • Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C • Hyperekplexia 1;Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C • Inborn genetic diseases	Uncertain significance (Nov 15, 2023)
14-66508569-A-C		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (May 17, 2022)
14-66508569-A-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Aug 16, 2022)
14-66508576-G-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 11, 2023)
14-66508584-C-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jun 14, 2022)
14-66508587-T-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jul 08, 2022)
14-66508594-A-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Dec 01, 2023)
14-66508597-C-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Nov 22, 2022)
14-66508597-C-G		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Dec 21, 2023)
14-66508597-C-T		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (Aug 10, 2023)
14-66508598-G-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jul 17, 2023)
14-66508599-G-C		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Benign (Jan 26, 2024)
14-66508600-G-C		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (May 20, 2022)
14-66508601-G-A		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jan 22, 2023)
14-66508607-G-C		Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Likely benign (Jan 11, 2022)
14-66680999-GA-G			Benign (May 13, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GPHN	protein_coding	protein_coding	ENST00000478722	23	674396

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000186	125726	1	15	125742	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.44	239	443	0.540	0.0000241	5007
Missense in Polyphen		92	221.81	0.41478		2436
Synonymous	0.205	143	146	0.978	0.00000749	1558
Loss of Function	5.72	3	43.9	0.0683	0.00000240	494

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000181	0.000119
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.000360	0.000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules. Catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released. {ECO:0000269|PubMed:26613940}.
• Disease: DISEASE: Molybdenum cofactor deficiency, complementation group C (MOCODC) [MIM:615501]: A form of molybdenum cofactor deficiency, an autosomal recessive metabolic disorder leading to the pleiotropic loss of molybdoenzyme activities. It is clinically characterized by onset in infancy of poor feeding, intractable seizures, severe psychomotor retardation, and death in early childhood in most patients. {ECO:0000269|PubMed:11095995, ECO:0000269|PubMed:22040219, ECO:0000269|PubMed:26613940}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Folate biosynthesis - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Splicing factor NOVA regulated synaptic proteins;GABA receptor Signaling;gamma-aminobutyric acid receptor life cycle pathway;Metabolism;Molybdenum cofactor biosynthesis;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;molybdenum cofactor biosynthesis (Consensus)

Recessive Scores

• pRec: 0.409

Intolerance Scores

• loftool: 0.0473
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.74

Haploinsufficiency Scores

• pHI: 0.138
• hipred: Y
• hipred_score: 0.728
• ghis: 0.570

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.881

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gphn
• Phenotype: cellular phenotype; vision/eye 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); 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); normal phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: Mo-molybdopterin cofactor biosynthetic process;establishment of synaptic specificity at neuromuscular junction;response to metal ion;molybdenum incorporation into molybdenum-molybdopterin complex;molybdopterin cofactor biosynthetic process;oxidation-reduction process;glycine receptor clustering;gamma-aminobutyric acid receptor clustering;postsynaptic neurotransmitter receptor diffusion trapping
• Cellular component: cytoplasm;cytosol;cytoskeleton;plasma membrane;postsynaptic density;cell junction;dendrite;postsynaptic membrane;postsynaptic specialization;postsynaptic specialization membrane
• Molecular function: protein binding;ATP binding;nitrate reductase activity;molybdopterin cofactor binding;metal ion binding;molybdopterin adenylyltransferase activity;molybdopterin molybdotransferase activity