IGHMBP2

protein-coding

immunoglobulin mu DNA binding protein 2, the group of UPF1 like RNA helicases|Zinc fingers AN1-type

Gene summary

This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002180.3

Inheritance

ClinVar variants

P:201U:539B:437

Top phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 1; Charcot-Marie-Tooth disease, axonal, type 2S

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr11:68,903,863-68,940,602

External References & Databases

Ensembl (ENSG00000132740)

Transcript & Mutation Effects

hg38 • Region Span ~36.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive distal spinal muscular atrophy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011436

Submitter: G2P

hereditary peripheral neuropathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020127

Submitter: ClinGen

IGHMBP2 was first reported in 2001 as a cause of autosomal recessive distal hereditary motor neuronopathy VI (DHMN6), also referred to as Spinal Muscular Atrophy with Respiratory Distress (SMARD1) (Grohmann et al., 2001; PMID: 11528396). In 2014, variants in IGHMBP2 were reported in patients with autosomal recessive Charcot Marie Tooth disease, axonal, type 2S (CMT2S) who displayed no signs of respiratory distress (Cottenie et al., 2014; PMID: 25439726). Per criteria outlined by the ClinGen Lumping and Splitting Working group, SMARD1 (OMIM: 604320) and CMT2S (OMIM: 616155) were lumped into the single disease entity, hereditary peripheral neuropathy (MONDO:0020127), to account for the disease spectrum associated with variants in this gene. No discrepancies were found between the inheritance pattern and the molecular mechanism, as both were identified as autosomal recessive and loss-of-function. This mechanism of pathogenicity is reinforced by functional evidence derived from Western blot analysis showing a significant reduction in protein expression (PMID: 25439726). IGHMBP2 encodes an ATP-dependent RNA/DNA helicase that binds DNA from the immunoglobulin mu chain switch region. It is highly conserved and believed to be involved in the regulation of DNA replication, pre-mRNA splicing, transcription, and translation. Included in this curation are two publications that report a total of eleven variants within nine probands, giving a max score of 12 points for genetic evidence (PMID: 11528396, PMID: 25439726). Pathogenic variants were comprised of homozygous or compound heterozygous nonsense, missense, frameshift, and splice donor variants. Additionally, the gene-disease association was further supported by experimental evidence including expression data in motor neurons and patients, mouse models with neuromuscular degeneration phenotypes, and rescue in mouse models via AAV-mediated gene replacement therapy, providing a functional score of 5 points. (PMID: 7749225, PMID: 26601156, PMID: 15269181, PMID: 25439726). In summary, IGHMBP2 is definitively associated with autosomal recessive peripheral neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

autosomal recessive distal spinal muscular atrophy 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011436

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease axonal type 2SSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014511

Submitter: Ambry Genetics

autosomal recessive distal spinal muscular atrophy 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011436

Submitter: Orphanet

Charcot-Marie-Tooth disease axonal type 2SDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014511

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.

Charcot-Marie-Tooth disease axonal type 2SSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014511

Submitter: Orphanet

hereditary peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020127

Submitter: PanelApp Australia

autosomal recessive distal spinal muscular atrophy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011436

Submitter: Genomics England PanelApp

autosomal recessive distal spinal muscular atrophy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011436

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease axonal type 2SSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014511

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neuronopathy, distal hereditary motor, autosomal recessive 1; Charcot-Marie-Tooth disease, axonal, type 2SAR

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: 11528396; 14681881; 15290238; 16458836; 16765827; 17431882; 20859832; 21353777; 22157136; 25439726; 25568292

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGHMBP2 variants in ClinVar

31 Conditions Cataloged

Autosomal recessive distal spinal muscular atrophy 1Total: 1174

Charcot-Marie-Tooth disease axonal type 2STotal: 1151

not providedTotal: 368

Inborn genetic diseasesTotal: 316

Charcot-Marie-Tooth diseaseTotal: 141

not specifiedTotal: 134

IGHMBP2-related disorderTotal: 126

Distal spinal muscular atrophyTotal: 38

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002180.3. 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			10 clinvar	379 clinvar	7 clinvar	396
missense	8 clinvar	57 clinvar	514 clinvar	45 clinvar	6 clinvar	630
nonsense	21 clinvar	15 clinvar	6 clinvar			42
start loss		1 clinvar				1
frameshift	54 clinvar	17 clinvar	7 clinvar			78
splice donor/acceptor (+/-2bp)	7 clinvar	21 clinvar	2 clinvar			30
Total	90	111	539	424	13	1177

Highest pathogenic variant AF is 0.00034800646

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002180.3	RefSeq	NP_002171.2	15	MANE Select
ENST00000255078.8	Ensembl	ENSP00000255078.4	15	MANE Select
ENST00000539224.2	Ensembl	ENSP00000440465.2	6	Standard
ENST00000545146.1	Ensembl	ENSP00000456366.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA replication
DNA repair
DNA recombination
translation
DNA duplex unwinding

Molecular Function

tRNA binding
DNA binding
DNA helicase activity
single-stranded DNA binding
RNA binding

Cellular Component

nucleus
cytoplasm
membrane
axon
growth cone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000255078
Coding exons: 15
Length: 36761
Individuals with no LoFs: 125607
Homozygous LoFs: 0
Heterozygous LoFs: 141
Defined: 125748
p: 0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.176	580	592	0.980	0.0000399	6378
Missense (PolyPhen)		192	207.34	0.92604		2161
Synonymous	-1.40	287	258	1.11	0.0000188	2081
Loss of Function	1.81	31	43.9	0.706	0.00000283	464

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00039	0.00038	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00082	0.00082	rare
Finnish	0.00047	0.00042	rare
European (Non-Finnish)	0.00075	0.00072	rare
South Asian	0.00062	0.00042	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 5' to 3' helicase that unwinds RNA and DNA duplices in an ATP-dependent reaction. Acts as a transcription regulator. Required for the transcriptional activation of the flounder liver- type antifreeze protein gene. Exhibits strong binding specificity to the enhancer element B of the flounder antifreeze protein gene intron. Binds to the insulin II gene RIPE3B enhancer region. May be involved in translation (By similarity). DNA-binding protein specific to 5'-phosphorylated single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region. Preferentially binds to the 5'-GGGCT-3' motif. Interacts with tRNA-Tyr. Stimulates the transcription of the human neurotropic virus JCV. {ECO:0000250, ECO:0000269|PubMed:19158098, ECO:0000269|PubMed:19299493}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 2S (CMT2S) [MIM:616155]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:25439726}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.199

Intolerance Scores

LoFtool: 0.0776
RVIS EVS: 0.86
RVIS percentile EVS: 88.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.818

Gene Damage Prediction

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