ITM2B

protein-coding

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

Gene summary

Amyloid precursor proteins are processed by beta-secretase and gamma-secretase to produce beta-amyloid peptides which form the characteristic plaques of Alzheimer disease. This gene encodes a transmembrane protein which is processed at the C-terminus by furin or furin-like proteases to produce a small secreted peptide which inhibits the deposition of beta-amyloid. Mutations which result in extension of the C-terminal end of the encoded protein, thereby increasing the size of the secreted peptide, are associated with two neurogenerative diseases, familial British dementia and familial Danish dementia. [provided by RefSeq, Oct 2009]

MANE transcript

NM_021999.5

Inheritance

ClinVar variants

P:2U:112B:48

Top phenotype

Cerebral amyloid angiopathy, ITM2B-related, 1; Cerebral amyloid angiopathy, ITM2B-related, 2; Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr13:48,232,612-48,270,357

External References & Databases

Ensembl (ENSG00000136156)

Transcript & Mutation Effects

hg38 • Region Span ~37.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ABri amyloidosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008306

Submitter: Orphanet

retinal dystrophy with inner retinal dysfunction and ganglion cell anomaliesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014483

Submitter: G2P

ADan amyloidosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007297

Submitter: Orphanet

retinal dystrophy with inner retinal dysfunction and ganglion cell anomaliesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014483

Submitter: Labcorp Genetics (formerly Invitae)

retinal dystrophy with inner retinal dysfunction and ganglion cell anomaliesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014483

Submitter: Orphanet

ABri amyloidosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008306

Submitter: Genomics England PanelApp

retinal dystrophy with inner retinal dysfunction and ganglion cell anomaliesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014483

Submitter: Ambry Genetics

ABri amyloidosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008306

Submitter: ClinGen

Integral membrane protein 2B (*ITM2B*) was first reported in relation to autosomal dominant familial British dementia in 1999 (Vidal et al., PMID: 10391242). Features of *ITM2B* related disease can include but are not limited to: cerebral amyloid angiopathy, early onset dementia, ataxia, and in some families visual impairment has been reported. The age of onset is variable but can be as early as the third decade. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism, inheritance pattern, or phenotypic variability; therefore, the following disease entities have been lumped into one disease entities, familial British dementia (OMIM: 176500), and familial Danish dementia (OMIM: 117300). An isolated *ITM2B* - related ocular disease entity was first asserted in 2014 by Audo et. al; PMID: 24026677. At this time the isolated ocular disease entity (Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities; OMIM: 616079) is not being curated as there are too few cases to determine if it represents a truly distinct disease entity. 4 variants (3 stop-loss, and 1 insertion leading to a frame-shift that causes an extension of the protein) that have been reported in 4 probands in 4 publications (PMIDs: 10391242, 10781099, 39625954, 37038821) are included in this curation. Genetic evidence also includes segregation in 3 kindreds (PMIDs: 39625954, 10781099, 10391242). The mechanism of pathogenicity appears to involve the formation of amyloid deposits (PMIDs: 37280119). This gene-disease relationship is also supported by a rat model carrying a knock-in of the variant identified in the Danish kindred and recapitulates the major features of disease as well as expression data and co-immunoprecipitation data showing physical interaction with APP (PMIDs: 15983050, 41354963, 10391242). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Neurovascular GCEP on the meeting date September 23, 2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Cerebral amyloid angiopathy, ITM2B-related, 1; Cerebral amyloid angiopathy, ITM2B-related, 2; Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalitiesAD

Manifestation: Audiologic/Otolaryngologic; 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: 21610757; 7086452; 2364266; 10391242; 10781099; 11557758; 21048150; 24026677

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITM2B variants in ClinVar

10 Conditions Cataloged

not providedTotal: 154

Inborn genetic diseasesTotal: 27

ITM2B-related disorderTotal: 12

not specifiedTotal: 10

ABri amyloidosisTotal: 3

ADan amyloidosisTotal: 3

Retinal dystrophy with inner retinal dysfunction and ganglion cell anomaliesTotal: 2

Optic atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021999.5. 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	39 clinvar	4 clinvar	44
missense	1 clinvar		98 clinvar	4 clinvar	1 clinvar	104
nonsense			2 clinvar			2
start loss						0
frameshift	1 clinvar		6 clinvar			7
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	2	0	112	43	5	162

Highest pathogenic variant AF is 6.9137644e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021999.5	RefSeq	NP_068839.1	6	MANE Select
ENST00000647800.2	Ensembl	ENSP00000497221.1	6	MANE Select
ENST00000378549.5	Ensembl	ENSP00000367811.5	4	Standard
ENST00000378549.6	Ensembl	ENSP00000367811.5	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Biological Process

nervous system development
negative regulation of amyloid precursor protein biosynthetic process
cellular protein metabolic process

Molecular Function

amyloid-beta binding
protein binding
ATP binding

Cellular Component

Golgi membrane
extracellular region
extracellular space
Golgi apparatus
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378565
Coding exons: 6
Length: 29770
Individuals with no LoFs: 125705
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125713
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.04	107	142	0.754	0.00000708	1754
Missense (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

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)	0.000062	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.315

Intolerance Scores

LoFtool: 0.474
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.506

Gene Damage Prediction

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