JPH3

protein-coding

junctophilin 3, the group of Junctophilins

Gene summary

Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. CAG/CTG repeat expansion from normally 6-28 repeats to 40-59 repeats in the 3' UTR of this gene have been associated with Huntington disease-like 2 (HDL2). This gene is a member of the junctophilin gene family. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2016]

Previous symbols:

TNRC22

MANE transcript

NM_020655.4

Inheritance

AR, AD

ClinVar variants

U:187B:68

Top phenotype

Huntington disease-like 2

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr16:87,601,835-87,698,156

External References & Databases

Ensembl (ENSG00000154118)

Transcript & Mutation Effects

hg38 • Region Span ~96.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Huntington disease-like 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011671

Submitter: Labcorp Genetics (formerly Invitae)

Huntington disease-like 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011671

Submitter: Ambry Genetics

Huntington disease-like 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011671

Submitter: Orphanet

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Huntington disease-like 2AD

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: 11694876; 11761463; 11914418; 11940688; 12805114; 14557581; 18816802; 19735092; 22367996; 22971727

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to JPH3 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 181

not providedTotal: 62

JPH3-related disorderTotal: 13

not specifiedTotal: 9

Huntington disease-like 2Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020655.4. 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			3 clinvar	30 clinvar	20 clinvar	53
missense			182 clinvar	17 clinvar	1 clinvar	200
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	187	47	21	255

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020655.4	RefSeq	NP_065706.2	5	MANE Select
ENST00000284262.3	Ensembl	ENSP00000284262.2	5	MANE Select
NM_001271604.4	RefSeq	NP_001258533.1	2	Standard
NM_001271605.3	RefSeq	NP_001258534.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

learning
memory
exploration behavior
locomotion
regulation of synaptic plasticity

Molecular Function

molecular_function
calcium-release channel activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
junctional sarcoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000284262
Coding exons: 5
Length: 96322
Individuals with no LoFs: 111669
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 111670
p: 0.00000448

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.318	511	491	1.04	0.0000360	4745
Missense (PolyPhen)		118	151.96	0.77654		1345
Synonymous	-5.09	324	227	1.43	0.0000178	1526
Loss of Function	4.29	1	23.4	0.0427	0.00000101	275

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000010	0.000010	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH3 is brain- specific and appears to have an active role in certain neurons involved in motor coordination and memory.;
Disease: DISEASE: Huntington disease-like 2 (HDL2) [MIM:606438]: Huntington disease (HD) is a neurodegenerative disorder resulting primarily from the loss of medium spiny projection neurons in the striatum, especially in the caudate nucleus, and, to a lesser extent, atrophy of mesencephalic and cortical structures. The typical clinical picture of HD combines familial adult onset chorea and subcortical dementia that usually begin during the fourth decade of life. {ECO:0000269|PubMed:11914418, ECO:0000269|PubMed:14557581}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.264

Intolerance Scores

RVIS EVS: -1.23
RVIS percentile EVS: 5.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.760

Gene Damage Prediction

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