NHLH2

nescient helix-loop-helix 2, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 1:115836377-115843917

Previous symbols: [ "HEN2" ]

Links

ENSG00000177551 ∙ NCBI:4808 ∙ OMIM:162361 ∙ HGNC:7818 ∙ Uniprot:Q02577 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 27 without anosmia (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 27 without anosmia	AR	Endocrine	In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease	Endocrine	35066646

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NHLH2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NHLH2 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						0
missense			9			9
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	9	0	0

Variants in NHLH2

This is a list of pathogenic ClinVar variants found in the NHLH2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-115838138-G-A		Hypogonadotropic hypogonadism 27 without anosmia • Hypogonadotropic hypogonadism	Uncertain significance (-)
1-115838188-T-C		not specified	Uncertain significance (Feb 20, 2025)
1-115838219-T-C		not specified	Uncertain significance (Apr 07, 2023)
1-115838254-G-T		not specified	Uncertain significance (Apr 07, 2023)
1-115838282-C-T		Hypogonadotropic hypogonadism	Uncertain significance (-)
1-115838290-T-G		not specified	Uncertain significance (Aug 27, 2024)
1-115838320-T-G		not specified	Uncertain significance (Feb 14, 2025)
1-115838338-T-C		not specified	Uncertain significance (Feb 27, 2023)
1-115838342-A-C		not specified	Uncertain significance (Jul 28, 2021)
1-115838347-G-A		Hypogonadotropic hypogonadism	Uncertain significance (-)
1-115838348-C-A		Hypogonadotropic hypogonadism	Uncertain significance (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NHLH2	protein_coding	protein_coding	ENST00000369506	1	7541

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.580	0.381	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.05	50	75.6	0.661	0.00000350	840
Missense in Polyphen		9	32.644	0.2757		352
Synonymous	-1.04	43	35.1	1.22	0.00000169	285
Loss of Function	1.52	0	2.68	0.00	1.18e-7	33

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.
• Pathway: Prader-Willi and Angelman Syndrome (Consensus)

Recessive Scores

• pRec: 0.136

Intolerance Scores

• rvis_EVS: 0.12
• rvis_percentile_EVS: 62.38

Haploinsufficiency Scores

• pHI: 0.644
• hipred: Y
• hipred_score: 0.544
• ghis: 0.667

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.307

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nhlh2
• Phenotype: homeostasis/metabolism phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); renal/urinary system phenotype; skeleton phenotype; digestive/alimentary 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); reproductive system phenotype

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;central nervous system development;mating behavior;cell differentiation;ovulation cycle;positive regulation of transcription by RNA polymerase II;positive regulation of DNA-binding transcription factor activity
• Cellular component: nucleus;transcription factor complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II activating transcription factor binding;DNA-binding transcription activator activity, RNA polymerase II-specific;protein binding;protein dimerization activity