ITM2B

integral membrane protein 2B, the group of BRICHOS domain containing

Basic information

Region (hg38): 13:48232612-48270357

Links

ENSG00000136156 ∙ NCBI:9445 ∙ OMIM:603904 ∙ HGNC:6174 ∙ Uniprot:Q9Y287 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ABri amyloidosis (Strong), mode of inheritance: AD
• ABri amyloidosis (Supportive), mode of inheritance: AD
• ADan amyloidosis (Supportive), mode of inheritance: AD
• retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (Supportive), mode of inheritance: AD
• retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (Limited), mode of inheritance: AD
• retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (Limited), mode of inheritance: AD
• retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral amyloid angiopathy, ITM2B-related, 1; Cerebral amyloid angiopathy, ITM2B-related, 2; Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities	AD	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	Audiologic/Otolaryngologic; Neurologic; Ophthalmologic	21610757; 7086452; 2364266; 10391242; 10781099; 11557758; 21048150; 24026677

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ITM2B gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITM2B 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				29	3	32
missense			61	3	1	65
nonsense			1			1
start loss						0
frameshift			4			4
inframe indel			3	1		4
splice donor/acceptor (+/-2bp)			1			1
splice region			4	3		7
non coding				7		7
Total	0	0	70	40	4

Variants in ITM2B

This is a list of pathogenic ClinVar variants found in the ITM2B region.

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

Position	Type	Phenotype	Significance	ClinVar
13-48233375-G-C			Likely benign (Jan 12, 2024)
13-48233380-A-G			Uncertain significance (Sep 19, 2023)
13-48233383-C-A			Uncertain significance (Sep 14, 2023)
13-48233399-G-A			Likely benign (Oct 17, 2022)
13-48233402-G-A			Likely benign (Feb 01, 2024)
13-48233403-G-A			Uncertain significance (Oct 13, 2023)
13-48233408-G-C			Uncertain significance (May 09, 2022)
13-48233410-A-G		ADan amyloidosis	Uncertain significance (May 02, 2018)
13-48233415-G-A		not specified	Uncertain significance (Jul 27, 2023)
13-48233419-C-T			Uncertain significance (Dec 27, 2021)
13-48233425-G-A		Inborn genetic diseases	Uncertain significance (Sep 14, 2023)
13-48233438-G-A			Likely benign (Jan 18, 2022)
13-48233441-C-T		not specified	Benign (Jan 30, 2024)
13-48233445-A-G			Uncertain significance (Jul 03, 2023)
13-48233446-T-TC			Uncertain significance (Jun 02, 2022)
13-48233448-C-T		Inborn genetic diseases • ITM2B-related disorder	Conflicting classifications of pathogenicity (Jan 16, 2024)
13-48233449-C-T			Uncertain significance (Sep 07, 2022)
13-48233450-C-T			Likely benign (Apr 13, 2022)
13-48233452-C-A			Benign (Jan 31, 2024)
13-48233452-C-G		Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies;ABri amyloidosis;ADan amyloidosis	Uncertain significance (Nov 06, 2023)
13-48233453-C-T			Likely benign (Aug 20, 2022)
13-48233454-G-T		Inborn genetic diseases • ITM2B-related disorder	Uncertain significance (Feb 23, 2023)
13-48233460-G-A			Uncertain significance (May 19, 2022)
13-48233465-G-T			Likely benign (Aug 05, 2023)
13-48233476-A-G			Uncertain significance (Jan 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ITM2B	protein_coding	protein_coding	ENST00000378565	6	29770

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.626	0.373	125705	0	8	125713	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.04	107	142	0.754	0.00000708	1754
Missense in Polyphen		24	41.217	0.58229		504
Synonymous	0.871	41	48.7	0.841	0.00000238	484
Loss of Function	2.64	2	11.8	0.170	5.59e-7	159

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)	0.0000618	0.0000616
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites.; FUNCTION: Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.
• Disease: DISEASE: Cerebral amyloid angiopathy, ITM2B-related 1 (CAA-ITM2B1) [MIM:176500]: A disorder characterized by amyloid deposition in the walls of cerebral blood vessels and neurodegeneration in the central nervous system. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Clinical features include progressive mental deterioration, spasticity and muscular rigidity. {ECO:0000269|PubMed:10391242, ECO:0000269|PubMed:10526337, ECO:0000269|PubMed:14656991}. Note=The disease is caused by mutations affecting the gene represented in this entry. A single base substitution at the stop codon of ITM2B generates a 277-residue precursor that is cleaved at the normal furin processing site to generate the ABri amyloidogenic peptide (PubMed:10391242). ABri accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. ABri peptide variant forms fibrils in vitro (PubMed:10526337). {ECO:0000269|PubMed:10391242, ECO:0000269|PubMed:10526337}.; DISEASE: Cerebral amyloid angiopathy, ITM2B-related 2 (CAA-ITM2B2) [MIM:117300]: A disorder characterized by amyloid deposition in the walls of the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord and retina. Plaques and neurofibrillary tangles are observed in the hippocampus. Clinical features include progressive ataxia, dementia, cataracts and deafness. {ECO:0000269|PubMed:10781099, ECO:0000269|PubMed:14656991, ECO:0000269|PubMed:16091362}. Note=The disease is caused by mutations affecting the gene represented in this entry. A decamer duplication in the 3' region of ITM2B results in the production of the ADan amyloidogenic peptide (PubMed:10781099). ADan is generated by cleavage of the mutated precursor at the normal furin processing site. ADan accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. {ECO:0000269|PubMed:10781099}.; DISEASE: Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities (RDGCA) [MIM:616079]: An autosomal dominant retinal dystrophy characterized by inner retinal dysfunction in association with ganglion cell abnormalities. Clinical features include mild photophobia, progressive loss of central vision, night blindness, and hyperreflectivity of nerve and ganglion cell layers. {ECO:0000269|PubMed:24026677}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: IL2 (Consensus)

Recessive Scores

• pRec: 0.315

Intolerance Scores

• loftool: 0.474
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.88

Haploinsufficiency Scores

• pHI: 0.229
• hipred: Y
• hipred_score: 0.825
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.506

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Itm2b
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: nervous system development;negative regulation of amyloid precursor protein biosynthetic process;cellular protein metabolic process
• Cellular component: Golgi membrane;extracellular region;extracellular space;Golgi apparatus;plasma membrane;endosome membrane;membrane;Golgi-associated vesicle membrane;integral component of organelle membrane;intracellular membrane-bounded organelle;extracellular exosome
• Molecular function: amyloid-beta binding;protein binding;ATP binding