KBTBD13

protein-coding

kelch repeat and BTB domain containing 13, the group of BTB domain containing

Gene summary

The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined. [provided by RefSeq, Jun 2010]

MANE transcript

NM_001101362.3

Inheritance

AD, AR

ClinVar variants

P:5U:449B:249

Top phenotype

Nemaline myopathy 6

gnomAD constraint

pLI —, LoF o/e 1.31

Max pathogenic AF

—

Genomic locus

chr15:65,076,746-65,079,948

External References & Databases

Ensembl (ENSG00000234438)

Transcript & Mutation Effects

hg38 • Region Span ~3.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nemaline myopathy 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012237

Submitter: ClinGen

*KBTBD13* was first reported in relation to autosomal dominant nemaline myopathy 6 in 2010 (Sambuughin N, et al., 2010, PMID: 21109227). At least 12 unique missense variants, and 1 nonsense variant, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 16 probands in 8 publications (PMIDs: 31671076, 21109227, 31828823, 29382405, 30208948, 33693846, 33742414, 38968056). Variants in this gene segregated with disease in 49 additional family members. This gene-disease association is supported by its enhanced expression in skeletal muscle (PMID: 21109227), its role in relaxation of skeletal muscle where it interacts with actin (PMID: 31671076), and a knock-in mouse model which recapitulated human disease (PMID: 31671076).In summary, *KBTBD13* is definitively associated with autosomal dominant nemaline myopathy 6. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the CM GCEP on 06/22/2020. It was reevaluated on 01/21/2025. As a result of this reevaluation new genetic evidence (PMIDs:33693846, 33742414, 38968056) was identified and the classification increased from Moderate to Definitive.

hereditary peripheral neuropathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0020127

Submitter: PanelApp Australia

nemaline myopathy 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012237

Submitter: PanelApp Australia

childhood-onset nemaline myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015738

Submitter: Orphanet

nemaline myopathy 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012237

Submitter: Ambry Genetics

nemaline myopathy 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012237

Submitter: G2P

nemaline myopathy 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012237

Submitter: Labcorp Genetics (formerly Invitae)

nemaline myopathy 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012237

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nemaline myopathy 6AD

Manifestation: 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: 11731279; 21104864; 21109227

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KBTBD13 variants in ClinVar

8 Conditions Cataloged

Nemaline myopathy 6Total: 638

Inborn genetic diseasesTotal: 128

not providedTotal: 92

not specifiedTotal: 55

KBTBD13-related disorderTotal: 20

Actin accumulation myopathyTotal: 1

Colorectal cancer, susceptibility to, 12Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001101362.3. 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			35 clinvar	145 clinvar	3 clinvar	183
missense	1 clinvar	3 clinvar	368 clinvar	81 clinvar	11 clinvar	464
nonsense			15 clinvar	1 clinvar		16
start loss			1 clinvar	2 clinvar		3
frameshift		1 clinvar	30 clinvar	5 clinvar	1 clinvar	37
splice donor/acceptor (+/-2bp)						0
Total	1	4	449	234	15	703

Highest pathogenic variant AF is 0.0000044128615

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001101362.3	RefSeq	NP_001094832.1	1	MANE Select
ENST00000432196.5	Ensembl	ENSP00000388723.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation

Biological Process

protein ubiquitination
post-translational protein modification

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000432196
Coding exons: 1
Length: 3123
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	-0.587	307	279	1.10	0.0000220	2765
Missense (PolyPhen)		94	92.834	1.0126		1011
Synonymous	-1.44	168	146	1.15	0.0000135	997
Loss of Function	-0.915	13	9.89	1.31	5.12e-7	99

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: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex. {ECO:0000269|PubMed:22542517}.;
Disease: DISEASE: Nemaline myopathy 6 (NEM6) [MIM:609273]: A form of nemaline myopathy characterized by childhood onset of slowly progressive proximal muscle weakness, exercise intolerance, and slow movements with stiff muscles. Patients are unable to run or correct themselves from falling over. {ECO:0000269|PubMed:21109227}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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