PCDH12

protocadherin 12, the group of Non-clustered protocadherins

Basic information

Region (hg38): 5:141943580-141969741

Links

ENSG00000113555 ∙ NCBI:51294 ∙ OMIM:605622 ∙ HGNC:8657 ∙ Uniprot:Q9NPG4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• diencephalic-mesencephalic junction dysplasia syndrome 1 (Definitive), mode of inheritance: AR
• diencephalic-mesencephalic junction dysplasia syndrome 1 (Strong), mode of inheritance: AR
• diencephalic-mesencephalic junction dysplasia (Supportive), mode of inheritance: AR
• diencephalic-mesencephalic junction dysplasia syndrome 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly, seizures, spasticity, and brain calcifications (MISSBC)	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	27164683; 28804758

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCDH12 gene.

• not provided (307 variants)
• Inborn genetic diseases (58 variants)
• Diencephalic-mesencephalic junction dysplasia syndrome 1 (34 variants)
• Diencephalic-mesencephalic junction dysplasia (3 variants)
• not specified (1 variants)
• Marshall syndrome (1 variants)
• Neurodevelopmental disorder (1 variants)
• Abnormal facial shape;Exudative retinopathy;Cerebellar ataxia;Dystonic disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCDH12 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			1	71	13	85
missense		2	169	21	19	211
nonsense	8	4	2			14
start loss						0
frameshift	3	3	2			8
inframe indel			5	2	4	11
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding				3	3	6
Total	11	9	179	97	39

Highest pathogenic variant AF is 0.00000657

Variants in PCDH12

This is a list of pathogenic ClinVar variants found in the PCDH12 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-141945390-CCTG-C		PCDH12-related disorder	Likely benign (Dec 06, 2022)
5-141945390-C-CCTG			Uncertain significance (Jan 02, 2022)
5-141945390-C-CCTGCTG			Benign (Jan 29, 2024)
5-141945390-C-CCTGCTGCTG		Diencephalic-mesencephalic junction dysplasia syndrome 1 • PCDH12-related disorder	Benign (Jan 31, 2024)
5-141945390-C-CCTGCTGCTGCTG			Benign (Jan 26, 2024)
5-141945390-C-CCTGCTGCTGCTGCTG			Uncertain significance (Jun 07, 2022)
5-141945401-T-TGCTGCTGCTGCTGCC			Uncertain significance (Oct 12, 2021)
5-141945401-T-TGCTGCTGCTGCTGCTGCC			Likely benign (Jan 29, 2024)
5-141945407-T-TGCTGCTGCC			Uncertain significance (Jul 12, 2021)
5-141945414-G-C			Uncertain significance (Dec 21, 2023)
5-141945416-T-C		Inborn genetic diseases	Uncertain significance (May 23, 2023)
5-141945420-G-T			Likely benign (Feb 22, 2023)
5-141945423-C-G			Benign (Nov 04, 2023)
5-141945431-C-T		Inborn genetic diseases	Uncertain significance (Feb 06, 2023)
5-141945432-C-T			Likely benign (Aug 09, 2022)
5-141945433-G-A			Uncertain significance (Aug 16, 2022)
5-141945468-T-A			Likely benign (Nov 07, 2023)
5-141945469-G-A			Uncertain significance (Jan 22, 2024)
5-141945469-G-C			Uncertain significance (Jan 18, 2021)
5-141945486-C-T			Likely benign (Sep 27, 2023)
5-141945491-C-A		Diencephalic-mesencephalic junction dysplasia syndrome 1	Uncertain significance (Jul 19, 2018)
5-141945502-G-A			Uncertain significance (Aug 17, 2022)
5-141945510-G-A			Likely benign (Jul 05, 2022)
5-141945511-C-T			Uncertain significance (Jul 26, 2022)
5-141945516-C-T			Likely benign (Apr 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCDH12	protein_coding	protein_coding	ENST00000231484	4	26155

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.85e-13	0.669	125669	0	79	125748	0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.784	622	680	0.915	0.0000386	7669
Missense in Polyphen		211	239.49	0.88105		2923
Synonymous	1.02	270	292	0.924	0.0000171	2540
Loss of Function	1.65	25	35.6	0.702	0.00000212	375

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000656	0.000655
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000544	0.000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000354	0.000352
Middle Eastern	0.000544	0.000544
South Asian	0.000229	0.000229
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions (By similarity). Acts as a regulator of cell migration, probably via increasing cell-cell adhesion (PubMed:21402705). Promotes homotypic calcium-dependent aggregation and adhesion and clusters at intercellular junctions (By similarity). Unable to bind to catenins, weakly associates with the cytoskeleton (By similarity). {ECO:0000250|UniProtKB:O55134, ECO:0000269|PubMed:21402705}.
• Disease: DISEASE: Microcephaly, seizures, spasticity, and brain calcifications (MISSBC) [MIM:251280]: An autosomal recessive syndrome characterized by congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and severe global developmental delay with profound intellectual disability, spasticity or dystonia. Brain imaging shows intracerebral calcifications. {ECO:0000269|PubMed:27164683, ECO:0000269|PubMed:28804758}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.112

Intolerance Scores

• loftool: 0.791
• rvis_EVS: 0.75
• rvis_percentile_EVS: 86.42

Haploinsufficiency Scores

• pHI: 0.601
• hipred: N
• hipred_score: 0.282
• ghis: 0.500

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.182

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pcdh12
• Phenotype: normal phenotype; vision/eye phenotype

Gene ontology

• Biological process: glycogen metabolic process;cell adhesion;homophilic cell adhesion via plasma membrane adhesion molecules;neuron recognition;calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules;labyrinthine layer development
• Cellular component: plasma membrane;integral component of plasma membrane;cell-cell junction;extracellular exosome
• Molecular function: calcium ion binding