TWIST2

protein-coding

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

Gene summary

The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001271893.4

Inheritance

AD, AR

ClinVar variants

P:6U:26B:10

Top phenotype

Ablepharon-macrostomia syndrome; Barber-Say syndrome; Focal facial dermal dysplasia 3, Setleis type

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr2:238,848,032-238,910,534

External References & Databases

Ensembl (ENSG00000233608)

Transcript & Mutation Effects

hg38 • Region Span ~62.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ablepharon macrostomia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008693

Submitter: Orphanet

focal facial dermal dysplasia type IIISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009203

Submitter: Orphanet

Barber-Say syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008853

Submitter: Orphanet

focal facial dermal dysplasia type IIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009203

Submitter: Labcorp Genetics (formerly Invitae)

Barber-Say syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008853

Submitter: Labcorp Genetics (formerly Invitae)

Barber-Say syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008853

Submitter: PanelApp Australia

focal facial dermal dysplasia type IIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009203

Submitter: PanelApp Australia

ablepharon macrostomia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008693

Submitter: PanelApp Australia

ablepharon macrostomia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008693

Submitter: Labcorp Genetics (formerly Invitae)

ablepharon macrostomia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008693

Submitter: G2P

focal facial dermal dysplasia type IIISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009203

Submitter: G2P

Clinical Genomic Database (CGD)

Ablepharon-macrostomia syndrome; Barber-Say syndrome; Focal facial dermal dysplasia 3, Setleis typeAD/AR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal

Intervention: General

Rationale: 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

Refs: 1867254; 2036354; 3631024; 4412216; 8368246; 8746822; 8818454; 11038439; 11807864; 12210295; 15103726; 16650233; 14069095; 20799330; 20830793; 20691403; 21801849; 21931173; 26119818

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TWIST2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 18

Inborn genetic diseasesTotal: 16

not specifiedTotal: 4

Focal facial dermal dysplasia type IIITotal: 3

Barber-Say syndromeTotal: 3

TWIST2-related disorderTotal: 2

Ablepharon macrostomia syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001271893.4. 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			1 clinvar	10 clinvar		11
missense	3 clinvar		24 clinvar			27
nonsense	2 clinvar		1 clinvar			3
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)						0
Total	6	0	26	10	0	42

Highest pathogenic variant AF is 0.0000056867007

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001271893.4	RefSeq	NP_001258822.1	1	MANE Select
ENST00000612363.2	Ensembl	ENSP00000482581.1	1	MANE Select
NM_057179.3	RefSeq	NP_476527.1	1	Standard
ENST00000448943.2	Ensembl	ENSP00000405176.2	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Proteoglycans in cancer - Homo sapiens (human)
EMT transition in Colorectal Cancer
Transcriptional regulation by RUNX2
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

multicellular organism development
cell differentiation
positive regulation of cell migration
negative regulation of apoptotic process
negative regulation of osteoblast differentiation

Molecular Function

DNA binding
protein binding
protein dimerization activity

Cellular Component

nucleus
nucleolus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000448943
Coding exons: 1
Length: 39221
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.13	33	89.9	0.367	0.00000412	1042
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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