TWNK

twinkle mtDNA helicase, the group of DNA helicases

Basic information

Region (hg38): 10:100987366-100994403

Previous symbols: [ "IOSCA", "C10orf2" ]

Links

ENSG00000107815 ∙ NCBI:56652 ∙ OMIM:606075 ∙ HGNC:1160 ∙ Uniprot:Q96RR1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (Supportive), mode of inheritance: AR
• Perrault syndrome (Supportive), mode of inheritance: AR
• autosomal dominant progressive external ophthalmoplegia (Supportive), mode of inheritance: AD
• mitochondrial DNA depletion syndrome, hepatocerebrorenal form (Supportive), mode of inheritance: AR
• mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (Strong), mode of inheritance: AR
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Perrault syndrome 5	AR	Biochemical	Individuals may have biochemical manifestations, including fasting hypoglycemia responsive to glucose therapy	Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal	8133312; 7719341; 10522883; 11431692; 12210792; 16135556; 17921179; 17722119; 18775955; 18971204; 20479361; 20880070; 21519523; 21681116; 21689831; 22353293; 22928142; 23375728; 25355836

ClinVar

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

• not provided (361 variants)
• Infantile onset spinocerebellar ataxia (88 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (83 variants)
• Autosomal recessive cerebellar ataxia (76 variants)
• Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (70 variants)
• not specified (34 variants)
• Hereditary spastic paraplegia (20 variants)
• Perrault syndrome (8 variants)
• Perrault syndrome 5 (8 variants)
• Ataxia Neuropathy Spectrum Disorders (6 variants)
• Mitochondrial disease (6 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions (6 variants)
• Mitochondrial DNA depletion syndrome (6 variants)
• See cases (4 variants)
• TWNK-related condition (3 variants)
• mitochondrial hepatopathy (3 variants)
• Auditory neuropathy (2 variants)
• Perrault syndrome 5;Infantile onset spinocerebellar ataxia (2 variants)
• Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Perrault syndrome 5;Infantile onset spinocerebellar ataxia;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (1 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1 variants)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic (1 variants)
• 8 conditions (1 variants)
• TWNK-related disorder (1 variants)
• Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Infantile onset spinocerebellar ataxia;Perrault syndrome 5;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (1 variants)
• Infantile onset spinocerebellar ataxia;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3;Perrault syndrome 5 (1 variants)
• Infantile onset spinocerebellar ataxia;Perrault syndrome 5 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TWNK 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			8	84		92
missense	8	22	180	3	1	214
nonsense	5	6	1			12
start loss						0
frameshift	5	4	3			12
inframe indel			3			3
splice donor/acceptor (+/-2bp)						0
splice region			4	2	2	8
non coding			28	19	8	55
Total	18	32	223	106	9

Highest pathogenic variant AF is 0.0000131

Variants in TWNK

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

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

Position	Type	Phenotype	Significance	ClinVar
10-100987379-T-C		not specified	Uncertain significance (Jan 24, 2024)
10-100987392-C-T		not specified	Uncertain significance (Jan 19, 2022)
10-100987561-A-G		Infantile onset spinocerebellar ataxia • Autosomal recessive cerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Conflicting classifications of pathogenicity (Apr 01, 2023)
10-100987567-A-T		Infantile onset spinocerebellar ataxia • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Autosomal recessive cerebellar ataxia	Uncertain significance (Jan 12, 2018)
10-100987589-C-T		Autosomal recessive cerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 12, 2018)
10-100987606-G-T		not specified • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Infantile onset spinocerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Autosomal recessive cerebellar ataxia	Benign (Jan 13, 2018)
10-100987619-C-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Autosomal recessive cerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Infantile onset spinocerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Perrault syndrome 5;Infantile onset spinocerebellar ataxia;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Uncertain significance (Jul 14, 2021)
10-100987626-T-G		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Autosomal recessive cerebellar ataxia • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987627-G-C		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Autosomal recessive cerebellar ataxia • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987662-G-A		Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Autosomal recessive cerebellar ataxia • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987741-G-A		Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Autosomal recessive cerebellar ataxia • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987788-C-T		Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Infantile onset spinocerebellar ataxia • Autosomal recessive cerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987793-C-T		Autosomal recessive cerebellar ataxia • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Infantile onset spinocerebellar ataxia	Uncertain significance (Jan 13, 2018)
10-100987903-CTG-C		Ataxia Neuropathy Spectrum Disorders • Progressive external ophthalmoplegia with mitochondrial DNA deletions • Autosomal recessive cerebellar ataxia • Mitochondrial DNA depletion syndrome	Likely benign (Apr 29, 2021)
10-100987907-G-A		Autosomal recessive cerebellar ataxia • Infantile onset spinocerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Uncertain significance (Jan 13, 2018)
10-100987921-G-C		Infantile onset spinocerebellar ataxia • Autosomal recessive cerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Conflicting classifications of pathogenicity (Jan 13, 2018)
10-100987970-C-T		Autosomal recessive cerebellar ataxia • Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis • Infantile onset spinocerebellar ataxia • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Likely benign (Dec 05, 2018)
10-100988106-T-C		Mitochondrial DNA depletion syndrome • Progressive external ophthalmoplegia with mitochondrial DNA deletions • Ataxia Neuropathy Spectrum Disorders • Autosomal recessive cerebellar ataxia	Uncertain significance (Jun 14, 2016)
10-100988222-C-A			Likely benign (Oct 14, 2023)
10-100988226-C-A			Likely benign (Oct 18, 2023)
10-100988226-C-T			Pathogenic (Mar 11, 2022)
10-100988230-G-T			Uncertain significance (Apr 25, 2022)
10-100988239-C-A			Uncertain significance (Jun 20, 2023)
10-100988240-C-G			Likely benign (Nov 03, 2023)
10-100988240-C-T		not specified	Likely benign (Oct 19, 2015)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TWNK	protein_coding	protein_coding	ENST00000311916	5	7035

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00323	0.997	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.61	301	390	0.771	0.0000268	4423
Missense in Polyphen		36	88.758	0.4056		1095
Synonymous	-0.617	166	156	1.06	0.00000928	1464
Loss of Function	3.42	10	30.3	0.330	0.00000258	258

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000275	0.000275
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000163	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.000163	0.000163
South Asian	0.0000654	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in mitochondrial DNA (mtDNA) metabolism. Could function as an adenine nucleotide-dependent DNA helicase. Function inferred to be critical for lifetime maintenance of mtDNA integrity. In vitro, forms in combination with POLG, a processive replication machinery, which can use double-stranded DNA (dsDNA) as template to synthesize single-stranded DNA (ssDNA) molecules. May be a key regulator of mtDNA copy number in mammals. {ECO:0000269|PubMed:15167897}.
• Disease: DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: A severe disease associated with mitochondrial dysfunction. Some patients are affected by progressive atrophy of the cerebellum, brain stem, the spinal cord, and sensory axonal neuropathy. Clinical features include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural hearing deficit, sensory axonal neuropathy, epileptic encephalopathy and female hypogonadism. In some individuals liver dysfunction and multi- organ failure is present. {ECO:0000269|PubMed:16135556, ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault syndrome, a sex-influenced disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. {ECO:0000269|PubMed:25355836}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mitochondrial biogenesis (Consensus)

Recessive Scores

• pRec: 0.154

Intolerance Scores

• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.97

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.775
• ghis: 0.578

Essentials

• essential_gene_gene_trap: N

Mouse Genome Informatics

• Gene name: Twnk
• 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); 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); embryo phenotype; cellular phenotype

Gene ontology

• Biological process: mitochondrial DNA replication;DNA unwinding involved in DNA replication;mitochondrial transcription;mitochondrion organization;protein hexamerization;protein homooligomerization;cellular response to glucose stimulus
• Cellular component: mitochondrial matrix;mitochondrial nucleoid
• Molecular function: protease binding;single-stranded DNA binding;ATP binding;5'-3' DNA helicase activity