MPDZ

protein-coding

multiple PDZ domain crumbs cell polarity complex component, the group of Crumbs complex|PDZ domain containing

Gene summary

The protein encoded by this gene has multiple PDZ domains, which are hallmarks of protein-protein interactions. The encoded protein is known to interact with the HTR2C receptor and may cause it to clump at the cell surface. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MANE transcript

NM_001378778.1

Inheritance

ClinVar variants

P:150U:972B:484

Top phenotype

Hydrocephalus, congenital, 2, with or without brain or eye anomalies

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr9:13,105,706-13,279,692

External References & Databases

Ensembl (ENSG00000107186)

Transcript & Mutation Effects

hg38 • Region Span ~174.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hydrocephalus, nonsyndromic, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: Ambry Genetics

hydrocephalus, nonsyndromic, autosomal recessive 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

hydrocephalus, nonsyndromic, autosomal recessive 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: G2P

hydrocephalus, nonsyndromic, autosomal recessive 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: Genomics England PanelApp

hydrocephalus, nonsyndromic, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: Labcorp Genetics (formerly Invitae)

hydrocephalus, nonsyndromic, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014085

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hydrocephalus, congenital, 2, with or without brain or eye anomaliesAR

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: 23240096

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MPDZ variants in ClinVar

13 Conditions Cataloged

not providedTotal: 1731

Inborn genetic diseasesTotal: 433

MPDZ-related disorderTotal: 120

Hydrocephalus, nonsyndromic, autosomal recessive 2Total: 106

not specifiedTotal: 84

Meniere diseaseTotal: 7

Fetal anomalies with a likely genetic causeTotal: 2

Paediatric disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378778.1. 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			14 clinvar	394 clinvar	7 clinvar	415
missense		2 clinvar	942 clinvar	69 clinvar	14 clinvar	1027
nonsense	33 clinvar	18 clinvar	4 clinvar			55
start loss			1 clinvar			1
frameshift	37 clinvar	21 clinvar	1 clinvar			59
splice donor/acceptor (+/-2bp)		39 clinvar	10 clinvar			49
Total	70	80	972	463	21	1606

Highest pathogenic variant AF is 0.00020198624

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378778.1	RefSeq	NP_001365707.1	46	MANE Select
ENST00000319217.12	Ensembl	ENSP00000320006.7	46	MANE Select
NM_001261406.2	RefSeq	NP_001248335.1	45	Standard
NM_001261407.2	RefSeq	NP_001248336.1	44	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)

Biological Process

cell adhesion
viral process

Molecular Function

protein binding
protein C-terminus binding

Cellular Component

cytoplasm
bicellular tight junction
postsynaptic density
apical plasma membrane
apicolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000541718
Coding exons: 45
Length: 173887
Individuals with no LoFs: 124419
Homozygous LoFs: 0
Heterozygous LoFs: 288
Defined: 124707
p: 0.00116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.98	1312	1.04e+3	1.26	0.0000530	13163
Missense (PolyPhen)		491	422.11	1.1632		5098
Synonymous	-3.71	466	375	1.24	0.0000198	4033
Loss of Function	2.47	73	99.6	0.733	0.00000560	1246

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0013	notable
Latino/Admixed American	0.0018	0.0018	notable
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.0013	0.0012	notable
Finnish	0.0011	0.0011	notable
European (Non-Finnish)	0.0011	0.0010	notable
South Asian	0.00084	0.00082	rare
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Interacts with HTR2C and provokes its clustering at the cell surface (By similarity). Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses. {ECO:0000250, ECO:0000269|PubMed:11150294, ECO:0000269|PubMed:15312654}.;
Disease: DISEASE: Hydrocephalus, congenital, 2, with or without brain or eye anomalies (HYC2) [MIM:615219]: A form of congenital hydrocephalus, a disease characterized by onset in utero of enlarged ventricles due to accumulation of ventricular cerebrospinal fluid. HYC2 affected individuals have variable neurologic impairement. Some individuals have other brain abnormalities, including lissencephaly, thinning of the corpus callosum, and neuronal heterotopia. Most patients have delayed motor development and some have delayed intellectual development and/or seizures. Additional congenital features, including cardiac septal defects, iris coloboma, and non-specific dysmorphic features, may be observed. HYC2 inheritance is autosomal recessive. {ECO:0000269|PubMed:23240096}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.998
RVIS EVS: 1.39
RVIS percentile EVS: 94.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

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