UBQLN2

ubiquilin 2, the group of Ubiquilin family

Basic information

Region (hg38): X:56563627-56567868

Links

ENSG00000188021 ∙ NCBI:29978 ∙ OMIM:300264 ∙ HGNC:12509 ∙ Uniprot:Q9UHD9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis type 15 (Strong), mode of inheritance: XL
• amyotrophic lateral sclerosis type 15 (Strong), mode of inheritance: XL
• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis type 15 (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia	XL	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	21857683; 24771548

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the UBQLN2 gene.

• Amyotrophic lateral sclerosis type 15 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the UBQLN2 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			4	39	7	50
missense	2	2	82	3	4	93
nonsense						0
start loss						0
frameshift						0
inframe indel			1	1		2
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			11	2		13
Total	2	2	98	45	11

Variants in UBQLN2

This is a list of pathogenic ClinVar variants found in the UBQLN2 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-56563711-G-T		Amyotrophic Lateral Sclerosis, Dominant • Amyotrophic lateral sclerosis type 15	Benign/Likely benign (Jan 13, 2018)
X-56563715-A-G		Amyotrophic lateral sclerosis type 15	Uncertain significance (Apr 27, 2017)
X-56563818-G-GCT		Amyotrophic Lateral Sclerosis, Dominant	Uncertain significance (Jun 14, 2016)
X-56563820-T-G		Amyotrophic lateral sclerosis type 15	Uncertain significance (Jan 13, 2018)
X-56563870-C-T			Uncertain significance (Jul 01, 2024)
X-56563877-G-T		Amyotrophic lateral sclerosis type 15	Uncertain significance (Mar 08, 2022)
X-56563894-C-G		Amyotrophic lateral sclerosis type 15	Uncertain significance (Jul 26, 2021)
X-56563922-C-T		Amyotrophic lateral sclerosis type 15	Uncertain significance (Jul 07, 2022)
X-56563924-T-A		Amyotrophic lateral sclerosis type 15	Benign (Jun 26, 2023)
X-56563929-C-T		Amyotrophic lateral sclerosis type 15	Uncertain significance (Apr 14, 2021)
X-56563942-G-A		Amyotrophic lateral sclerosis type 15	Uncertain significance (Dec 12, 2023)
X-56563949-G-T		Amyotrophic lateral sclerosis type 15	Uncertain significance (Dec 10, 2023)
X-56563955-G-C		Amyotrophic lateral sclerosis type 15 • UBQLN2-related disorder	Uncertain significance (Jan 07, 2022)
X-56563984-G-T		UBQLN2-related disorder	Likely benign (Aug 12, 2024)
X-56564011-C-T		Amyotrophic lateral sclerosis type 15	Likely benign (Sep 23, 2022)
X-56564014-G-A		UBQLN2-related disorder	Likely benign (Jun 23, 2023)
X-56564017-G-A			Likely benign (May 01, 2023)
X-56564023-G-A		Amyotrophic lateral sclerosis type 15	Likely benign (Aug 08, 2023)
X-56564032-G-T		Amyotrophic lateral sclerosis type 15	Likely benign (Jun 19, 2023)
X-56564038-G-A		Amyotrophic lateral sclerosis type 15	Likely benign (Jun 26, 2023)
X-56564053-G-T		Amyotrophic lateral sclerosis type 15	Uncertain significance (Nov 22, 2023)
X-56564059-G-A		Amyotrophic lateral sclerosis type 15	Likely benign (Oct 09, 2022)
X-56564068-C-T		Amyotrophic lateral sclerosis type 15	Likely benign (Oct 01, 2023)
X-56564075-C-G		UBQLN2-related disorder	Uncertain significance (Jul 04, 2024)
X-56564116-A-G		Amyotrophic Lateral Sclerosis, Dominant • Amyotrophic lateral sclerosis type 15	Conflicting classifications of pathogenicity (Jun 05, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
UBQLN2	protein_coding	protein_coding	ENST00000338222	1	3418

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.850	0.150	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.50	172	237	0.726	0.0000159	4112
Missense in Polyphen		30	53.899	0.5566		1067
Synonymous	-1.51	116	97.0	1.20	0.00000675	1312
Loss of Function	2.73	1	10.6	0.0943	6.79e-7	156

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin- proteasome system (UPS), autophagy and the endoplasmic reticulum- associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:10983987). Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:24215460, PubMed:18307982). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957). Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor- arrestin complexes concentrate in clathrin-coated pits (CCPs) (PubMed:18199683). {ECO:0000269|PubMed:10983987, ECO:0000269|PubMed:18199683, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:19148225, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:24215460}.
• Disease: DISEASE: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia. {ECO:0000269|PubMed:21857683, ECO:0000269|PubMed:22560112, ECO:0000269|PubMed:22717235, ECO:0000269|PubMed:22892309, ECO:0000269|PubMed:24215460, ECO:0000269|PubMed:25616961}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);Vesicle-mediated transport;Membrane Trafficking;Clathrin-mediated endocytosis;Cargo recognition for clathrin-mediated endocytosis (Consensus)

Recessive Scores

• pRec: 0.106

Intolerance Scores

• loftool: 0.131
• rvis_EVS: -0.36
• rvis_percentile_EVS: 28.63

Haploinsufficiency Scores

• pHI: 0.371
• hipred: Y
• hipred_score: 0.815
• ghis: 0.634

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.741

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ubqln2

Gene ontology

• Biological process: autophagy;regulation of macroautophagy;ubiquitin-dependent ERAD pathway;negative regulation of clathrin-dependent endocytosis;positive regulation of ER-associated ubiquitin-dependent protein catabolic process;negative regulation of G protein-coupled receptor internalization;regulation of autophagosome assembly
• Cellular component: nucleus;cytoplasm;autophagosome;cytosol;plasma membrane;cytoplasmic vesicle
• Molecular function: protein binding