USH2A

usherin, the group of USH2 complex |Fibronectin type III domain containing

Basic information

Region (hg38): 1:215622891-216423448

Previous symbols: [ "USH2" ]

Links

ENSG00000042781 ∙ NCBI:7399 ∙ OMIM:608400 ∙ HGNC:12601 ∙ Uniprot:O75445 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Usher syndrome type 2A (Strong), mode of inheritance: AR
• retinitis pigmentosa (Supportive), mode of inheritance: AD
• Usher syndrome type 2 (Supportive), mode of inheritance: AR
• Usher syndrome type 2A (Definitive), mode of inheritance: AR
• retinitis pigmentosa 39 (Strong), mode of inheritance: AR
• Usher syndrome type 2A (Strong), mode of inheritance: AR
• Usher syndrome type 2 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Usher syndrome, type 2A	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; It has been suggested that that stapes surgery should not be performed due to a high likelihood of complications (the use of cochlear implants has been reported as beneficial)	Audiologic/Otolaryngologic; Ophthalmologic	1580321; 9624053; 10775529; 10729113; 12427073; 15015129; 16301217; 16098008; 15671307; 17085681; 17296898; 18273898; 19881469; 20440071; 20301515

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the USH2A gene.

• not_provided (7348 variants)
• Usher_syndrome_type_2A (2445 variants)
• Retinitis_pigmentosa_39 (1768 variants)
• Retinal_dystrophy (827 variants)
• not_specified (676 variants)
• Inborn_genetic_diseases (526 variants)
• Retinitis_pigmentosa (313 variants)
• Usher_syndrome (248 variants)
• USH2A-related_disorder (191 variants)
• Rare_genetic_deafness (93 variants)
• Usher_syndrome_type_2 (71 variants)
• Hearing_impairment (23 variants)
• Cone-rod_dystrophy (9 variants)
• Leber_congenital_amaurosis (8 variants)
• Retinitis_Pigmentosa,_Recessive (7 variants)
• Retinitis_pigmentosa-deafness_syndrome (7 variants)
• See_cases (6 variants)
• Ear_malformation (6 variants)
• Autosomal_recessive_retinitis_pigmentosa (6 variants)
• Congenital_sensorineural_hearing_impairment (4 variants)
• Monogenic_hearing_loss (4 variants)
• Autosomal_dominant_nonsyndromic_hearing_loss_36 (4 variants)
• Nonsyndromic_genetic_hearing_loss (3 variants)
• Visual_impairment (3 variants)
• Hypoplasia_of_the_brainstem (2 variants)
• Motor_delay (2 variants)
• Delayed_speech_and_language_development (2 variants)
• Progressive_cone_dystrophy_(without_rod_involvement) (2 variants)
• Usher_syndrome_type_1 (2 variants)
• Congenital_stationary_night_blindness (2 variants)
• Childhood_onset_hearing_loss (2 variants)
• Cerebellar_hemisphere_hypoplasia (2 variants)
• Cone-rod_dystrophy_3 (2 variants)
• Retinal_disorders (2 variants)
• Amblyopia (2 variants)
• Optic_atrophy (2 variants)
• Joubert_syndrome (2 variants)
• Retinal_degeneration (2 variants)
• Congenital_cerebellar_hypoplasia (2 variants)
• Retinal_pigment_epithelial_atrophy (1 variants)
• Hearing_loss (1 variants)
• Usher_syndrome_type_3A (1 variants)
• Deafness (1 variants)
• Rod-cone_dystrophy (1 variants)
• Pigmentary_retinopathy (1 variants)
• Prostate_cancer (1 variants)
• Hearing_loss,_autosomal_recessive (1 variants)
• Macular_dystrophy (1 variants)
• Blindness (1 variants)
• Sensorineural_hearing_loss_disorder (1 variants)
• Bardet-Biedl_syndrome (1 variants)
• Abnormal_macular_morphology (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the USH2A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000206933.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	9	75	2327	28	2441
missense	90	379	2722	252	27	3470
nonsense	347	224	3			574
start loss		1				1
frameshift	449	336	6			791
splice donor/acceptor (+/-2bp)	85	202	5	1		293
Total	973	1151	2811	2580	55

Highest pathogenic variant AF is 0.0014603126

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
USH2A	protein_coding	protein_coding	ENST00000307340	71	800503

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.57e-94	0.0000512	124962	1	785	125748	0.00313

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-2.47	3076	2.71e+3	1.13	0.000147	33915
Missense in Polyphen		902	832.76	1.0831		10397
Synonymous	-4.00	1174	1.01e+3	1.16	0.0000584	10217
Loss of Function	3.46	178	235	0.756	0.0000120	2941

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00672	0.00660
Ashkenazi Jewish	0.00119	0.00119
East Asian	0.00310	0.00299
Finnish	0.00148	0.00148
European (Non-Finnish)	0.00324	0.00323
Middle Eastern	0.00310	0.00299
South Asian	0.00399	0.00393
Other	0.00474	0.00473

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in hearing and vision.
• Disease: DISEASE: Usher syndrome 2A (USH2A) [MIM:276901]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH2 is characterized by congenital mild hearing impairment with normal vestibular responses. {ECO:0000269|PubMed:10729113, ECO:0000269|PubMed:10738000, ECO:0000269|PubMed:10909849, ECO:0000269|PubMed:11311042, ECO:0000269|PubMed:12112664, ECO:0000269|PubMed:12525556, ECO:0000269|PubMed:14970843, ECO:0000269|PubMed:15015129, ECO:0000269|PubMed:15025721, ECO:0000269|PubMed:15241801, ECO:0000269|PubMed:15325563, ECO:0000269|PubMed:17085681, ECO:0000269|PubMed:17405132, ECO:0000269|PubMed:18273898, ECO:0000269|PubMed:18452394, ECO:0000269|PubMed:19683999, ECO:0000269|PubMed:19737284, ECO:0000269|PubMed:20309401, ECO:0000269|PubMed:20440071, ECO:0000269|PubMed:20507924, ECO:0000269|PubMed:21593743, ECO:0000269|PubMed:21686329, ECO:0000269|PubMed:22004887, ECO:0000269|PubMed:23737954, ECO:0000269|PubMed:26377068, ECO:0000269|PubMed:9624053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 39 (RP39) [MIM:613809]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:10775529, ECO:0000269|PubMed:12112664, ECO:0000269|PubMed:12427073, ECO:0000269|PubMed:15325563, ECO:0000269|PubMed:16098008, ECO:0000269|PubMed:17296898, ECO:0000269|PubMed:20507924, ECO:0000269|PubMed:21686329, ECO:0000269|PubMed:22334370, ECO:0000269|PubMed:24227914}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in USH2A has been found in a patient with a form of non-syndromic sensorineural hearing loss. {ECO:0000269|PubMed:25388789}.

Intolerance Scores

• loftool: 0.924
• rvis_EVS: 4.18
• rvis_percentile_EVS: 99.71

Haploinsufficiency Scores

• pHI: 0.158
• hipred: Y
• hipred_score: 0.543

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0777

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Ush2a
• 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); hearing/vestibular/ear phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: ush2a
• Affected structure: eye photoreceptor cell
• Phenotype tag: abnormal
• Phenotype quality: apoptotic

Gene ontology

• Biological process: visual perception;sensory perception of sound;hair cell differentiation;establishment of protein localization;photoreceptor cell maintenance;maintenance of animal organ identity;response to stimulus;sensory perception of light stimulus;inner ear receptor cell differentiation
• Cellular component: photoreceptor inner segment;stereocilia ankle link;stereocilia ankle link complex;basement membrane;cytoplasm;integral component of membrane;apical plasma membrane;photoreceptor connecting cilium;stereocilium bundle;ciliary basal body;neuronal cell body;terminal bouton;stereocilium membrane;periciliary membrane compartment;USH2 complex
• Molecular function: protein binding;collagen binding;myosin binding;protein homodimerization activity