pontocerebellar hypoplasia type 2A

Summary

pontocerebellar hypoplasia type 2A (MONDO:0010190) is a disease caused by TSEN54 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TSEN54 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 2A
Mondo ID	MONDO:0010190
MeSH	C564738
OMIM	277470
DOID	DOID:0060267
UMLS	C1848526
MedGen	376379
GARD	0015244
Is cancer (heuristic)	no

Also known as: microcephaly pontocerebellar hypoplasia dyskinesia · PCH2A · pontocerebellar hypoplasia type 2 caused by mutation in TSEN54 · pontocerebellar hypoplasia, type 2A · TSEN54 pontocerebellar hypoplasia type 2

Data availability: 44 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › bulbospinal muscular atrophy › pontocerebellar hypoplasia type 2 › pontocerebellar hypoplasia type 2A

Related subtypes (4): pontocerebellar hypoplasia type 2B, pontocerebellar hypoplasia type 2C, pontocerebellar hypoplasia type 2D, pontocerebellar hypoplasia, type 2F

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

44 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 8 pathogenic/likely pathogenic, 7 benign, 6 conflicting classifications of pathogenicity, 6 pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454338	NM_207346.3(TSEN54):c.775C>T (p.Gln259Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2120	NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
212451	NM_207346.3(TSEN54):c.1386_1387insTA (p.Lys463Ter)	TSEN54	Pathogenic	criteria provided, single submitter
212452	NM_207346.3(TSEN54):c.1397dup (p.Gly467fs)	TSEN54	Pathogenic	criteria provided, single submitter
212454	NM_207346.3(TSEN54):c.823del (p.Val275fs)	TSEN54	Pathogenic	criteria provided, single submitter
2395121	NM_207346.3(TSEN54):c.856_862dup (p.Val288fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434304	NM_207346.3(TSEN54):c.789_798del (p.Leu264fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265282	NM_207346.3(TSEN54):c.670_671del (p.Lys224fs)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
2745042	NM_207346.3(TSEN54):c.767del (p.Gly256fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2843217	NM_207346.3(TSEN54):c.846_856del (p.Ala284fs)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2850363	NM_207346.3(TSEN54):c.505C>T (p.Arg169Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495240	NM_207346.3(TSEN54):c.371G>T (p.Gly124Val)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561138	NM_207346.3(TSEN54):c.940del (p.Leu314fs)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
620188	NM_207346.3(TSEN54):c.1039A>T (p.Lys347Ter)	TSEN54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121	TSEN54:c.[277T>C;919G>T]		Likely pathogenic	criteria provided, single submitter
3582828	NM_207346.3(TSEN54):c.80_102del (p.Arg27fs)	LOC112533671	Likely pathogenic	criteria provided, single submitter
4845811	NM_207346.3(TSEN54):c.743C>G (p.Ser248Ter)	TSEN54	Likely pathogenic	criteria provided, single submitter
638161	NM_207346.3(TSEN54):c.1535T>C (p.Phe512Ser)	TSEN54	Likely pathogenic	criteria provided, single submitter
1181537	NM_207346.3(TSEN54):c.766G>A (p.Gly256Ser)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1210718	NM_207346.3(TSEN54):c.1313G>A (p.Arg438Gln)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1219861	NM_207346.3(TSEN54):c.1136G>A (p.Arg379Gln)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160124	NM_207346.3(TSEN54):c.1114G>A (p.Val372Met)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212455	NM_207346.3(TSEN54):c.83C>T (p.Ser28Leu)	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
889594	NM_207346.3(TSEN54):c.369+5G>A	TSEN54	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029380	NM_207346.3(TSEN54):c.1280T>C (p.Leu427Pro)	TSEN54	Uncertain significance	criteria provided, single submitter
1033698	NM_207346.3(TSEN54):c.167G>A (p.Arg56His)	TSEN54	Uncertain significance	criteria provided, single submitter
1033699	NM_207346.3(TSEN54):c.637A>G (p.Lys213Glu)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033700	NM_207346.3(TSEN54):c.808C>T (p.Pro270Ser)	TSEN54	Uncertain significance	criteria provided, single submitter
1385645	NM_207346.3(TSEN54):c.946C>T (p.Arg316Cys)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts
1491165	NM_207346.3(TSEN54):c.1186C>T (p.Arg396Trp)	TSEN54	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TSEN54	Strong	Autosomal recessive	pontocerebellar hypoplasia type 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSEN54	Orphanet:166063	Pontocerebellar hypoplasia type 4
TSEN54	Orphanet:2524	Pontocerebellar hypoplasia type 2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
granulocyte	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSEN54	232	ubiquitous	marker	granulocyte, right uterine tube, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSEN54	1,085

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSEN54	Q7Z6J9	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA processing	1	356.9×	0.008	TSEN54
tRNA processing in the nucleus	1	196.9×	0.008	TSEN54
Metabolism of RNA	1	41.7×	0.024	TSEN54

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA-type intron splice site recognition and cleavage	1	5617.3×	5e-04	TSEN54
tRNA splicing, via endonucleolytic cleavage and ligation	1	1404.3×	0.001	TSEN54
mRNA processing	1	78.8×	0.013	TSEN54

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSEN54	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TSEN54	4.6.1.16	tRNA-intron lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TSEN54
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TSEN54	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.