PCDH12

protein-coding

protocadherin 12, the group of Non-clustered protocadherins

Gene summary

This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 6 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene localizes to the region on chromosome 5 where the protocadherin gene clusters reside. The exon organization of this transcript is similar to that of the gene cluster transcripts, notably the first large exon, but no significant sequence homology exists. The function of this cellular adhesion protein is undetermined but mouse protocadherin 12 does not bind catenins and appears to have no affect on cell migration or growth. [provided by RefSeq, Jul 2008]

MANE transcript

NM_016580.4

Inheritance

ClinVar variants

P:38U:259B:195

Top phenotype

Diencephalic-mesencephalic junction dysplasia syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr5:141,943,581-141,969,741

External References & Databases

Ensembl (ENSG00000113555)

Transcript & Mutation Effects

hg38 • Region Span ~26.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

diencephalic-mesencephalic junction dysplasia syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009625

Submitter: Ambry Genetics

diencephalic-mesencephalic junction dysplasia syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009625

Submitter: G2P

diencephalic-mesencephalic junction dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017868

Submitter: Orphanet

diencephalic-mesencephalic junction dysplasia syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009625

Submitter: Labcorp Genetics (formerly Invitae)

diencephalic-mesencephalic junction dysplasia syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009625

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Diencephalic-mesencephalic junction dysplasia syndrome 1AR

Manifestation: Neurologic

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: 27164683; 28804758

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDH12 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 362

Inborn genetic diseasesTotal: 189

Diencephalic-mesencephalic junction dysplasia syndrome 1Total: 41

not specifiedTotal: 21

PCDH12-related disorderTotal: 19

Diencephalic-mesencephalic junction dysplasiaTotal: 6

Disorder of development or morphogenesisTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016580.4. 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			1 clinvar	117 clinvar	8 clinvar	126
missense		3 clinvar	251 clinvar	54 clinvar	16 clinvar	324
nonsense	9 clinvar	11 clinvar	3 clinvar			23
start loss						0
frameshift	5 clinvar	10 clinvar	4 clinvar			19
splice donor/acceptor (+/-2bp)						0
Total	14	24	259	171	24	492

Highest pathogenic variant AF is 0.00011400333

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016580.4	RefSeq	NP_057664.1	4	MANE Select
ENST00000231484.4	Ensembl	ENSP00000231484.3	4	MANE Select
ENST00000510041.1	Ensembl	ENSP00000429094.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

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

Molecular Function

calcium ion binding

Cellular Component

plasma membrane
integral component of plasma membrane
cell-cell junction
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000231484
Coding exons: 4
Length: 26155
Individuals with no LoFs: 125669
Homozygous LoFs: 0
Heterozygous LoFs: 79
Defined: 125748
p: 0.000314

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.784	622	680	0.915	0.0000386	7669
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00054	0.00054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.182

Gene Damage Prediction

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