HECW2

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2, the group of HECT domain containing|C2 domain containing

Basic information

Region (hg38): 2:196189099-196593684

Links

ENSG00000138411 ∙ NCBI:57520 ∙ OMIM:617245 ∙ HGNC:29853 ∙ Uniprot:Q9P2P5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with hypotonia, seizures, and absent language (Definitive), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia, seizures, and absent language (Strong), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia, seizures, and absent language (Strong), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• complex neurodevelopmental disorder (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with hypotonia, seizures, and absent language	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	Craniofacial; Neurologic	27334371; 27389779

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HECW2 gene.

• Neurodevelopmental disorder with hypotonia, seizures, and absent language (4 variants)
• HECW2-related disorder (2 variants)
• Inborn genetic diseases (2 variants)
• Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HECW2 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			3	37	15	55
missense	4	25	151	49	10	239
nonsense			6			6
start loss						0
frameshift			2			2
inframe indel			1	1	1	3
splice donor/acceptor (+/-2bp)			2			2
splice region			1	7	2	10
non coding			1	2	6	9
Total	4	25	166	89	32

Variants in HECW2

This is a list of pathogenic ClinVar variants found in the HECW2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-196201240-C-A		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Benign (Aug 10, 2021)
2-196201282-C-T		Inborn genetic diseases	Likely pathogenic (Sep 08, 2017)
2-196201290-A-G		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Uncertain significance (Nov 08, 2019)
2-196201349-G-A			Likely benign (Jul 01, 2023)
2-196201354-G-A		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Conflicting classifications of pathogenicity (Sep 01, 2022)
2-196201379-T-A			Benign (Sep 01, 2023)
2-196201386-G-A			Likely benign (May 01, 2024)
2-196215912-T-G			Likely benign (Apr 01, 2023)
2-196215918-G-A		HECW2-related disorder	Benign/Likely benign (Jul 01, 2024)
2-196215922-C-T		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Uncertain significance (Feb 05, 2020)
2-196215958-C-G		Inborn genetic diseases	Pathogenic/Likely pathogenic (Nov 21, 2023)
2-196215961-G-T		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Likely pathogenic (Mar 17, 2021)
2-196215962-A-C		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Likely pathogenic (Oct 19, 2020)
2-196215965-T-C		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Likely pathogenic (Mar 17, 2021)
2-196217017-C-A		Inborn genetic diseases	Likely pathogenic (Jun 07, 2016)
2-196217025-G-A		Developmental disorder	Uncertain significance (Nov 19, 2021)
2-196217031-C-G		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Likely pathogenic (Jul 03, 2018)
2-196217042-C-A		Inborn genetic diseases	Uncertain significance (Jun 16, 2024)
2-196217055-C-T		Inborn genetic diseases	Uncertain significance (Sep 29, 2023)
2-196217066-C-T		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Conflicting classifications of pathogenicity (May 20, 2023)
2-196217067-G-A			Likely benign (Feb 01, 2024)
2-196220033-T-C		Inborn genetic diseases	Uncertain significance (Mar 27, 2024)
2-196220088-T-G			Likely benign (Jun 06, 2018)
2-196220089-G-A			Uncertain significance (Oct 24, 2017)
2-196220092-C-A		Neurodevelopmental disorder with hypotonia, seizures, and absent language	Likely pathogenic (Mar 17, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HECW2	protein_coding	protein_coding	ENST00000260983	28	399323

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000299	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.31	625	905	0.691	0.0000523	10311
Missense in Polyphen		149	346.65	0.42983		3824
Synonymous	0.777	323	341	0.947	0.0000202	3074
Loss of Function	6.98	13	80.6	0.161	0.00000475	865

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000174	0.000174
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.00	0.00
South Asian	0.000143	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of TP73. Acts to stabilize TP73 and enhance activation of transcription by TP73 (PubMed:12890487). Involved in the regulation of mitotic metaphase/anaphase transition (PubMed:24163370). {ECO:0000269|PubMed:12890487, ECO:0000269|PubMed:24163370}.
• Disease: DISEASE: Neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL) [MIM:617268]: A neurodevelopmental disorder characterized by severely delayed psychomotor development, absent speech, epilepsy, encephalopathy, hypotonia, dystonia/dyskinesia, and macrocephaly. Brain imaging show cerebral atrophy, enlarged ventricles, and white matter abnormalities. {ECO:0000269|PubMed:27389779}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Class I MHC mediated antigen processing & presentation (Consensus)

Recessive Scores

• pRec: 0.106

Intolerance Scores

• rvis_EVS: -2.47
• rvis_percentile_EVS: 0.98

Haploinsufficiency Scores

• pHI: 0.461
• hipred: Y
• hipred_score: 0.563
• ghis: 0.528

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.795

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hecw2
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;protein ubiquitination;regulation of mitotic metaphase/anaphase transition;proteasome-mediated ubiquitin-dependent protein catabolic process;positive regulation of protein catabolic process;regulation of dendrite morphogenesis;negative regulation of sodium ion transmembrane transporter activity
• Cellular component: cytoplasm;mitotic spindle
• Molecular function: protein binding;ubiquitin protein ligase activity