TPM2

tropomyosin 2, the group of Tropomyosins

Basic information

Region (hg38): 9:35681992-35690056

Previous symbols: [ "AMCD1" ]

Links

ENSG00000198467 ∙ NCBI:7169 ∙ OMIM:190990 ∙ HGNC:12011 ∙ Uniprot:P07951 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• arthrogryposis, distal, type 1A (Strong), mode of inheritance: AD
• digitotalar dysmorphism (Supportive), mode of inheritance: AD
• Sheldon-hall syndrome (Supportive), mode of inheritance: AD
• congenital fiber-type disproportion myopathy (Supportive), mode of inheritance: AD
• typical nemaline myopathy (Supportive), mode of inheritance: AD
• childhood-onset nemaline myopathy (Supportive), mode of inheritance: AD
• cap myopathy (Supportive), mode of inheritance: AD
• arthrogryposis, distal, type 1A (Strong), mode of inheritance: AD
• congenital myopathy 23 (Strong), mode of inheritance: AD
• TPM2-related myopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital myopathy 23; CAP myopathy 2; Arthrogryposis, distal, type 1A; Arthrogryposis, distal, type 2B	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	Cardiovascular; Craniofacial; Musculoskeletal	11738357; 12592607; 17434307; 17846275; 19047562; 19345583; 22084935; 22798622; 22832343

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TPM2 gene.

• not provided (8 variants)
• Arthrogryposis, distal, type 1A (6 variants)
• Congenital myopathy 23 (4 variants)
• TPM2-related disorder (2 variants)
• Arthrogryposis, distal, type 2B4 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPM2 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			1	45		46
missense	3	13	63	1		80
nonsense		1	1			2
start loss						0
frameshift	2	2	3			7
inframe indel	3	2	7			12
splice donor/acceptor (+/-2bp)	1	3				4
splice region		1	8	12	1	22
non coding			12	61	18	91
Total	9	21	87	107	18

Highest pathogenic variant AF is 0.00000657

Variants in TPM2

This is a list of pathogenic ClinVar variants found in the TPM2 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-35682107-T-C		Inborn genetic diseases	Uncertain significance (May 01, 2022)
9-35682110-G-C		Arthrogryposis, distal, type 1A • Congenital myopathy 23 • Distal arthrogryposis type 2B1	Uncertain significance (Mar 05, 2018)
9-35682160-G-C		Congenital myopathy with fiber type disproportion	Uncertain significance (Feb 22, 2019)
9-35682165-T-G		Congenital myopathy 23	Likely pathogenic (Oct 06, 2021)
9-35682258-G-C			Benign (Jun 19, 2018)
9-35682299-T-A			Benign (Jun 14, 2018)
9-35682300-T-C			Likely benign (Jun 28, 2018)
9-35682350-G-A			Likely benign (Jul 06, 2018)
9-35682873-C-T			Benign (Jan 01, 2023)
9-35682882-C-T			Benign (Oct 01, 2022)
9-35682960-G-A		Arthrogryposis, distal, type 1A • Congenital myopathy 23	Uncertain significance (Jan 13, 2018)
9-35682965-G-A		Congenital myopathy 23 • Arthrogryposis, distal, type 1A	Uncertain significance (Jan 12, 2018)
9-35683060-T-C		Arthrogryposis, distal, type 1A • Congenital myopathy 23	Uncertain significance (Jan 12, 2018)
9-35683134-T-G		Arthrogryposis, distal, type 1A • Congenital myopathy 23	Conflicting classifications of pathogenicity (Jan 12, 2018)
9-35683137-G-T		Congenital myopathy 23 • Arthrogryposis, distal, type 1A	Uncertain significance (Feb 02, 2018)
9-35683151-C-T		not specified • Congenital myopathy 23 • Arthrogryposis, distal, type 1A	Benign (Jan 13, 2018)
9-35683152-G-A		not specified • Congenital myopathy 23 • Arthrogryposis, distal, type 1A	Benign (Jan 12, 2018)
9-35683168-G-T		Arthrogryposis, distal, type 1A	Likely benign (Aug 01, 2023)
9-35683177-A-AT		TPM2-related disorder	Likely pathogenic (May 31, 2023)
9-35683182-G-A		Arthrogryposis, distal, type 1A	Uncertain significance (May 15, 2022)
9-35683184-G-A		Arthrogryposis, distal, type 1A	Uncertain significance (Jul 23, 2019)
9-35683185-C-T		Arthrogryposis, distal, type 1A	Uncertain significance (Mar 11, 2022)
9-35683198-C-T		Arthrogryposis, distal, type 1A	Likely benign (Nov 08, 2022)
9-35683201-G-A		Arthrogryposis, distal, type 1A • Congenital myopathy 23	Benign/Likely benign (Aug 27, 2023)
9-35683230-C-A		Congenital myopathy 23	Uncertain significance (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPM2	protein_coding	protein_coding	ENST00000378292	9	9029

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000239	0.983	125725	0	23	125748	0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.13	80	155	0.517	0.00000985	1867
Missense in Polyphen		30	76.216	0.39362		928
Synonymous	-0.186	68	66.1	1.03	0.00000448	505
Loss of Function	2.12	9	19.0	0.474	0.00000109	234

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000268	0.000268
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000704	0.0000703
Middle Eastern	0.000109	0.000109
South Asian	0.000163	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. The non-muscle isoform may have a role in agonist-mediated receptor internalization. {ECO:0000250|UniProtKB:P58774, ECO:0000250|UniProtKB:P58775}.
• Disease: DISEASE: Nemaline myopathy 4 (NEM4) [MIM:609285]: A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. Nemaline myopathy type 4 presents from infancy to childhood with hypotonia and moderate-to-severe proximal weakness with minimal or no progression. Major motor milestones are delayed but independent ambulation is usually achieved, although a wheelchair may be needed in later life. {ECO:0000269|PubMed:11738357, ECO:0000269|PubMed:17846275, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arthrogryposis, distal, 1A (DA1A) [MIM:108120]: A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. Distal arthrogryposis type 1 is characterized largely by camptodactyly and clubfoot. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. {ECO:0000269|PubMed:12592607, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cap myopathy 2 (CAPM2) [MIM:609285]: A rare congenital skeletal muscle disorder characterized by the presence of cap-like structures which are well demarcated and peripherally located under the sarcolemma and show abnormal accumulation of sarcomeric proteins. Clinical features are early onset of hypotonia and non- progressive or slowly progressive muscle weakness. Respiratory problems are common. {ECO:0000269|PubMed:17434307, ECO:0000269|PubMed:19047562, ECO:0000269|PubMed:19345583, ECO:0000269|PubMed:24692096}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arthrogryposis, distal, 2B (DA2B) [MIM:601680]: A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA2B is characterized by contractures of the hands and feet, and a distinctive face characterized by prominent nasolabial folds, small mouth and downslanting palpebral fissures. {ECO:0000269|PubMed:17339586}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Striated Muscle Contraction;Smooth Muscle Contraction;Striated Muscle Contraction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.224

Intolerance Scores

• loftool: 0.297
• rvis_EVS: -0.23
• rvis_percentile_EVS: 36.86

Haploinsufficiency Scores

• pHI: 0.812
• hipred: N
• hipred_score: 0.460
• ghis: 0.512

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.780

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tpm2

Gene ontology

• Biological process: muscle contraction;actin filament organization;muscle filament sliding;regulation of ATPase activity
• Cellular component: cytosol;muscle thin filament tropomyosin;actin filament;actin cytoskeleton
• Molecular function: actin binding;structural constituent of muscle;identical protein binding;protein homodimerization activity;protein heterodimerization activity;actin filament binding