TRAPPC6B

protein-coding

trafficking protein particle complex subunit 6B, the group of Trafficking protein particle complex subunits

Gene summary

TRAPPC6B is a component of TRAPP complexes, which are tethering complexes involved in vesicle transport (Kummel et al., 2005 [PubMed 16025134]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_001079537.2

Inheritance

ClinVar variants

P:13U:33B:16

Top phenotype

Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr14:39,147,811-39,170,532

External References & Databases

Ensembl (ENSG00000182400)

Transcript & Mutation Effects

hg38 • Region Span ~22.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: G2P

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: PanelApp Australia

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: Illumina

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: ClinGen

The *TRAPPC6B* gene is located on chromosome 14 at 14q21.1 and encodes the trafficking protein particle complex, subunit 6B protein, a core subunit of TRAPP II and TRAPP III complexes. *TRAPPC6B* was first reported in relation to autosomal recessive neurodevelopmental disorder with microcephaly, epilepsy and brain atrophy (NEDMEBA) in 2018 (Marin-Valencia et al., PMID: 28626029). NEDMEBA is characterized by severe intellectual disability, global developmental delay, microcephaly and short stature. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental evidence. To date, 6 splice site variants and 9 nonsense variants, including 10 unique and 5 recurrent variants in 38 patients have been reported in four publications. Two splice site variants and 4 nonsense variants from four publications are included in this curation (PMID 28626029, 28397838, 31687267, 37713627). This gene-disease relationship is supported by experimental evidence including functional alteration and rescue in patient cells, as well as data from zebrafish and drosophila models showing partial recapitulation of phenotype (PMID 37713627, 28626029). In summary, there is definitive evidence to support the relationship between *TRAPPC6B* and autosomal recessive NEDMEBA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date November 19, 2024 (SOP Version 11).

neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060640

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophyAR

Manifestation: Neurologic

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: 28397838; 28626029

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAPPC6B variants in ClinVar

5 Conditions Cataloged

not providedTotal: 38

Inborn genetic diseasesTotal: 21

Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophyTotal: 11

TRAPPC6B-related disorderTotal: 9

TRAPPC6B-related neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001079537.2. 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	13 clinvar	2 clinvar	16
missense			27 clinvar	1 clinvar		28
nonsense	2 clinvar	2 clinvar				4
start loss			1 clinvar			1
frameshift	2 clinvar	3 clinvar				5
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	4 clinvar			8
Total	6	7	33	14	2	62

Highest pathogenic variant AF is 0.000021182243

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001079537.2	RefSeq	NP_001073005.1	6	MANE Select
ENST00000330149.10	Ensembl	ENSP00000330289.5	6	MANE Select
NM_177452.4	RefSeq	NP_803235.1	5	Standard
ENST00000347691.9	Ensembl	ENSP00000335171.6	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Transport to the Golgi and subsequent modification

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
nervous system development
regulation of GTPase activity
COPII vesicle coating

Molecular Function

protein binding
Rab guanyl-nucleotide exchange factor activity

Cellular Component

Golgi membrane
endoplasmic reticulum
cis-Golgi network
trans-Golgi network
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330149
Coding exons: 6
Length: 22722
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125746
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.107	81	83.7	0.967	0.00000417	1035
Missense (PolyPhen)		31	26.911	1.1519		383
Synonymous	-1.47	42	31.5	1.33	0.00000172	276
Loss of Function	0.864	7	9.94	0.704	4.83e-7	126

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000067	0.000062	rare
Latino/Admixed American	0.00044	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00023	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00015	0.00013	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a transport protein particle (TRAPP) complex that may function in specific stages of inter-organelle traffic (PubMed:16025134, PubMed:16828797). Specifically involved in the early development of neural circuitry, likely by controlling the frequency and amplitude of intracellular calcium transients implicated in the regulation of neuron differentiation and survival (Probable). {ECO:0000269|PubMed:16025134, ECO:0000269|PubMed:16828797, ECO:0000305|PubMed:28626029}.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.533
RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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