SPEG

protein-coding

striated muscle enriched protein kinase, the group of I-set domain containing|Myosin light chain kinase family

Gene summary

This gene encodes a protein with similarity to members of the myosin light chain kinase family. This protein family is required for myocyte cytoskeletal development. Along with the desmin gene, expression of this gene may be controlled by the desmin locus control region. Mutations in this gene are associated with centronuclear myopathy 5. [provided by RefSeq, Jun 2016]

Previous symbols:

APEG1

MANE transcript

NM_005876.5

Inheritance

ClinVar variants

P:54U:1148B:836

Top phenotype

Centronuclear myopathy 5

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr2:219,434,843-219,493,629

External References & Databases

Ensembl (ENSG00000072195)

Transcript & Mutation Effects

hg38 • Region Span ~58.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy, centronuclear, 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014418

Submitter: G2P

myopathy, centronuclear, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014418

Submitter: PanelApp Australia

myopathy, centronuclear, 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014418

Submitter: ClinGen

Variants in the SPEG gene have been reported in nine probands with autosomal recessive centronuclear myopathy in five different publications. Thirteen unique variants predicted to cause a loss of function of the protein have been reported, suggesting homozygous loss of function is the mechanism of disease. This gene-disease relationship is further supported by both constitutive and muscle-specific mouse models and functional alteration, expression, and interaction studies. In summary, SPEG is definitively associated with autosomal recessive centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

myopathy, centronuclear, 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014418

Submitter: Ambry Genetics

autosomal recessive centronuclear myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015705

Submitter: Orphanet

myopathy, centronuclear, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014418

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Centronuclear myopathy 5AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition may include cardiomyopathy, and recognition may allow early management, which has been described as effectve in affected individuals

Refs: 25087613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPEG variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1854

Inborn genetic diseasesTotal: 579

not specifiedTotal: 234

Myopathy, centronuclear, 5Total: 145

SPEG-related disorderTotal: 100

SPEG-related congenital myopathyTotal: 2

Congenital myopathyTotal: 1

Primary dilated cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005876.5. 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			12 clinvar	745 clinvar	9 clinvar	766
missense			1123 clinvar	73 clinvar	9 clinvar	1205
nonsense	13 clinvar	8 clinvar	3 clinvar			24
start loss						0
frameshift	19 clinvar	8 clinvar	2 clinvar			29
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	8 clinvar			14
Total	33	21	1148	818	18	2038

Highest pathogenic variant AF is 0.00001303938

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005876.5	RefSeq	NP_005867.3	41	MANE Select
ENST00000312358.12	Ensembl	ENSP00000311684.7	41	MANE Select
NM_001173476.2	RefSeq	NP_001166947.1	4	Standard
NM_001438924.1	RefSeq	NP_001425853.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
muscle organ development
negative regulation of cell population proliferation
muscle cell differentiation
cardiovascular system development

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312358
Coding exons: 41
Length: 63442
Individuals with no LoFs: 124755
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 124815
p: 0.000240

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.78	1541	1.88e+3	0.820	0.000123	20326
Missense (PolyPhen)		555	775.27	0.71588		8341
Synonymous	1.01	799	836	0.956	0.0000553	7364
Loss of Function	8.24	27	127	0.212	0.00000716	1372

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0013	notable
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00017	0.00017	rare
Finnish	0.000095	0.000093	rare
European (Non-Finnish)	0.00021	0.00019	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.;
Disease: DISEASE: Myopathy, centronuclear, 5 (CNM5) [MIM:615959]: A form of centronuclear myopathy, a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. CNM5 features include severe neonatal hypotonia with respiratory insufficiency, difficulty feeding, and delayed motor development. Some patients die in infancy, and some develop dilated cardiomyopathy. {ECO:0000269|PubMed:25087613}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.507
RVIS EVS: -0.06
RVIS percentile EVS: 48.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.631

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High