TWIST2

twist family bHLH transcription factor 2, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 2:238848031-238910534

Links

ENSG00000233608 ∙ NCBI:117581 ∙ OMIM:607556 ∙ HGNC:20670 ∙ Uniprot:Q8WVJ9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ablepharon macrostomia syndrome (Strong), mode of inheritance: AD
• ablepharon macrostomia syndrome (Definitive), mode of inheritance: AD
• focal facial dermal dysplasia type III (Strong), mode of inheritance: AR
• ablepharon macrostomia syndrome (Supportive), mode of inheritance: AD
• Barber-Say syndrome (Supportive), mode of inheritance: AD
• focal facial dermal dysplasia type III (Supportive), mode of inheritance: AD
• Barber-Say syndrome (Strong), mode of inheritance: AD
• focal facial dermal dysplasia type III (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ablepharon-macrostomia syndrome; Barber-Say syndrome; Focal facial dermal dysplasia 3, Setleis type	AD/AR	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; Dermatologic; Musculoskeletal	1867254; 2036354; 3631024; 4412216; 8368246; 8746822; 8818454; 11038439; 11807864; 12210295; 15103726; 16650233; 14069095; 20799330; 20830793; 20691403; 21801849; 21931173; 26119818

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TWIST2 gene.

• Barber-Say syndrome (1 variants)
• not provided (1 variants)
• Focal facial dermal dysplasia type III (1 variants)
• Ablepharon macrostomia syndrome (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TWIST2 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				6		6
missense	2		10			12
nonsense	1					1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1		1
Total	3	0	10	7	0

Highest pathogenic variant AF is 0.0000197

Variants in TWIST2

This is a list of pathogenic ClinVar variants found in the TWIST2 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-238848244-C-T		not specified	Uncertain significance (Mar 11, 2024)
2-238848248-C-G			Likely benign (Dec 11, 2023)
2-238848278-G-A		TWIST2-related disorder	Likely benign (Oct 08, 2022)
2-238848283-A-C			Uncertain significance (Oct 13, 2021)
2-238848286-G-A			Uncertain significance (Mar 01, 2020)
2-238848298-G-A			Uncertain significance (-)
2-238848306-C-G		Inborn genetic diseases	Uncertain significance (May 30, 2024)
2-238848375-G-A		Inborn genetic diseases	Uncertain significance (Nov 17, 2022)
2-238848379-GC-G		Focal facial dermal dysplasia type III	Pathogenic (Oct 01, 2011)
2-238848407-G-A			Likely benign (Dec 28, 2018)
2-238848408-C-T		Focal facial dermal dysplasia type III	Pathogenic (Aug 13, 2010)
2-238848418-G-T			Uncertain significance (Mar 15, 2022)
2-238848438-G-A		Ablepharon macrostomia syndrome • Inborn genetic diseases	Pathogenic (Jun 07, 2020)
2-238848438-G-C		Barber-Say syndrome	Pathogenic (Aug 06, 2018)
2-238848439-A-C		Barber-Say syndrome	Pathogenic (Jul 02, 2015)
2-238848438-G-GAGCGCC		Barber-Say syndrome	Pathogenic (Jul 02, 2015)
2-238848464-C-T			Likely benign (Nov 13, 2017)
2-238848545-C-A			Likely benign (Mar 29, 2018)
2-238848570-C-T		Focal facial dermal dysplasia type III	Pathogenic (Aug 30, 2023)
2-238848571-A-G		Inborn genetic diseases	Uncertain significance (Nov 22, 2023)
2-238848575-C-T			Likely benign (Sep 12, 2018)
2-238848595-A-G		Inborn genetic diseases	Uncertain significance (Jun 23, 2023)
2-238848598-A-G			Uncertain significance (Oct 25, 2022)
2-238848629-C-G			Uncertain significance (Aug 27, 2019)
2-238848664-T-C		Inborn genetic diseases	Uncertain significance (May 09, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TWIST2	protein_coding	protein_coding	ENST00000448943	1	39221

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.560	0.394	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.13	33	89.9	0.367	0.00000412	1042
Missense in Polyphen		3	28.928	0.10371		354
Synonymous	1.88	25	40.2	0.622	0.00000191	311
Loss of Function	1.46	0	2.49	0.00	1.06e-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: Binds to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of proinflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism (By similarity). Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors. {ECO:0000250, ECO:0000269|PubMed:11062344}.
• Disease: DISEASE: Ablepharon-macrostomia syndrome (AMS) [MIM:200110]: A congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth. {ECO:0000269|PubMed:26119818}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Barber-Say syndrome (BBRSAY) [MIM:209885]: A rare ectodermal dysplasia characterized by ectropion, macrostomia, ear abnormalities, broad nasal bridge, bulbous nose, redundant skin, hypertrichosis, dental abnormalities, and variable other features. {ECO:0000269|PubMed:26119818}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);EMT transition in Colorectal Cancer;Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription (Consensus)

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.662
• ghis: 0.538

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Twist2
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system 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); normal phenotype; reproductive system phenotype; 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); hematopoietic system phenotype; hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye phenotype; homeostasis/metabolism phenotype; immune system phenotype; skeleton 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); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; cellular phenotype

Gene ontology

• Biological process: multicellular organism development;cell differentiation;positive regulation of cell migration;negative regulation of apoptotic process;negative regulation of osteoblast differentiation;negative regulation of transcription, DNA-templated
• Cellular component: nucleus;nucleolus;cytoplasm
• Molecular function: DNA binding;protein binding;protein dimerization activity