ESPN

protein-coding

espin, the group of Ankyrin repeat domain containing

Gene summary

This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

Previous symbols:

DFNB36

MANE transcript

NM_031475.3

Inheritance

AR, AD

ClinVar variants

P:40U:351B:174

Top phenotype

Deafness, autosomal dominant, without vestibular involvement; Deafness, autosomal recessive 36, with or without vestibular involvement; Usher syndrome, type 1M

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr1:6,424,776-6,461,367

External References & Databases

Ensembl (ENSG00000187017)

Transcript & Mutation Effects

hg38 • Region Span ~36.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 36DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012170

Submitter: G2P

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 36LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012170

Submitter: Ambry Genetics

Usher syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: Orphanet

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 36MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012170

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The ESPN gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 11/30/17. This association was made using case-level. At least 2 variants, a missense and an in-frame deletion, have been reported in humans. ESPN was first associated with this disease in humans as early as 2006 (Donaudy et al.). Association is seen in at least 2 probands in 1 publication (15930085). This gene-disease association is supported by a relevant expression study (15286153). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/18.

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The ESPN gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 11/29/2017. This association was made using case-level data only. At least 9 nonsense and frameshift variants have been reported in humans. ESPN was first associated with this disease in humans as early as 2004 (Naz et al.). Association is seen in at least 6 probands in 4 publications (15286153, 18973245, 26445815, 28281779). Variants in this gene segregated with disease in 14 additional family members. This gene-disease association is supported by a mouse model, a cell culture rescue model, expression studies and other relevant assays. Of note, missense variants and one in-frame deletion in this gene have been implicated in autosomal dominant nonsyndromic hearing loss. This has been assessed separately. In summary, ESPN is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.

Usher syndrome, type 1MLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032841

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 36STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012170

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome, type 1MLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032841

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant, without vestibular involvement; Deafness, autosomal recessive 36, with or without vestibular involvement; Usher syndrome, type 1MAD/AR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 15286153; 15930085; 18973245; 29572253

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ESPN variants in ClinVar

15 Conditions Cataloged

not providedTotal: 451

Inborn genetic diseasesTotal: 167

not specifiedTotal: 164

ESPN-related disorderTotal: 77

Autosomal recessive nonsyndromic hearing loss 36Total: 40

Usher syndrome, type 1MTotal: 20

Retinal dystrophyTotal: 11

Autosomal dominant nonsyndromic hearing loss 91Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031475.3. 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			5 clinvar	138 clinvar		143
missense		2 clinvar	335 clinvar	30 clinvar	4 clinvar	371
nonsense	2 clinvar	7 clinvar				9
start loss			1 clinvar			1
frameshift	7 clinvar	12 clinvar	2 clinvar	2 clinvar		23
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	8 clinvar			18
Total	12	28	351	170	4	565

Highest pathogenic variant AF is 0.000024142422

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031475.3	RefSeq	NP_113663.2	13	MANE Select
ENST00000645284.1	Ensembl	ENSP00000496593.1	13	MANE Select
NM_001367473.1	RefSeq	NP_001354402.1	14	Standard
NM_001367474.1	RefSeq	NP_001354403.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
locomotory behavior
parallel actin filament bundle assembly
actin filament bundle assembly
positive regulation of filopodium assembly

Molecular Function

SH3 domain binding
actin filament binding

Cellular Component

cytoplasm
microvillus
brush border
filamentous actin
stereocilium tip

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377828
Coding exons: 13
Length: 36583
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125743
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0787	440	435	1.01	0.0000266	5303
Missense (PolyPhen)		173	168.45	1.027		1821
Synonymous	0.805	183	197	0.927	0.0000131	1817
Loss of Function	1.83	18	28.6	0.630	0.00000128	358

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00012	rare
Latino/Admixed American	0.00076	0.00075	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000054	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.000093	0.000079	rare
South Asian	0.00036	0.00033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Multifunctional actin-bundling protein. Plays a major role in regulating the organization, dimension, dynamics and signaling capacities of the actin filament-rich microvilli in the mechanosensory and chemosensory cells. Required for the assembly and stabilization of the stereociliary parallel actin bundles. Plays a crucial role in the formation and maintenance of inner ear hair cell stereocilia. Involved in the elongation of actin in stereocilia. In extrastriolar hair cells, required for targeting MYO3B to stereocilia tips, and for regulation of stereocilia diameter and staircase formation. {ECO:0000250|UniProtKB:Q9ET47}.;
Disease: DISEASE: Deafness, autosomal recessive, 36, with or without vestibular involvement (DFNB36) [MIM:609006]: A form of non- syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB36 is characterized by prelingual, profound hearing loss, and vestibular areflexia in some patients. {ECO:0000269|PubMed:15286153, ECO:0000269|PubMed:15930085, ECO:0000269|PubMed:28281779}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.370

Gene Damage Prediction

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