GeneBe

CLN8

protein-coding

CLN8 transmembrane ER and ERGIC protein, the group of TLC domain containing

Gene summary

This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]

Previous symbols:
  • EPMR
  • C8orf61

MANE transcript

NM_018941.4

Inheritance

AR, AD

ClinVar variants

P:96U:245B:215

Top phenotype

Ceroid lipofuscinosis, neuronal, 8; Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr8:1,755,778-1,801,711

External References & Databases

Ensembl (ENSG00000182372)NCBI Gene (2055)OMIM (607837)HGNC:2079GenCCUniProt (Q9UBY8)AlphaFoldClinVar (CLN8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~45.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronal ceroid lipofuscinosis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

CLN8 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) in 1999 (Ranta et al., PMID: 10508524). At least 50 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 unrelated probands in 5 publications (PMID: 10508524, 15024724, 19201763, 19807737, 26075876). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. Of note, the founder variant c.70C>G p.R24G in CLN8 has been implicated in the Northern epilepsy variant of NCL, a slightly more mild and protracted presentation of NCL. Since these patients have intraneuronal brain pathology similar to other patients with classic NCLs (PMID: 10764041), we have “lumped” the conditions for curation. This gene-disease association is supported by a spontaneous non-human animal (dog) model with vision loss, ataxia, and spontaneous seizures (PMID: 24953404). In summary, CLN8 is definitively associated with autosomal recessive NCL. 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 Epilepsy Working Group on 9/1/20 (SOP Version 7).

neuronal ceroid lipofuscinosis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: Ambry Genetics

neuronal ceroid lipofuscinosis 8 northern epilepsy variantSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012391

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 8 northern epilepsy variantSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012391

Submitter: Orphanet

autism spectrum disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

neuronal ceroid lipofuscinosis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: Myriad Women's Health

neuronal ceroid lipofuscinosis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: Natera

neuronal ceroid lipofuscinosis 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010830

Submitter: G2P

Clinical Genomic Database (CGD)

Ceroid lipofuscinosis, neuronal, 8; Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variantAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

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: 10508524; 10191125; 11589000; 15024724; 15074367; 16570191; 17129765; 17560505; 19431184; 19807737; 21990111; 22220808; 22964447Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLN8 variants in ClinVar

12 Conditions Cataloged
Neuronal ceroid lipofuscinosisTotal: 482
Neuronal ceroid lipofuscinosis 8Total: 166
not providedTotal: 119
Inborn genetic diseasesTotal: 74
not specifiedTotal: 66
Neuronal ceroid lipofuscinosis 8 northern epilepsy variantTotal: 30
CLN8-related disorderTotal: 25
Intellectual disabilityTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018941.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
201
clinvar
1
clinvar
 205
missense
3
clinvar
27
clinvar
234
clinvar
10
clinvar
3
clinvar
 277
nonsense
22
clinvar
7
clinvar
2
clinvar
 31
start loss
2
clinvar
2
clinvar
 4
frameshift
14
clinvar
15
clinvar
2
clinvar
 31
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
4
clinvar
 8
Total42542452114556

Highest pathogenic variant AF is 0.000042136417

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_018941.4RefSeqNP_061764.22MANE Select
ENST00000331222.6EnsemblENSP00000328182.42MANE Select
ENST00000519254.2EnsemblENSP00000490016.12Standard
ENST00000519254.3EnsemblENSP00000490016.12Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Synaptic Vesicle Pathway

Biological Process

  • age-dependent response to oxidative stress
  • phospholipid metabolic process
  • ceramide metabolic process
  • lipid transport
  • mitochondrial membrane organization

Cellular Component

  • mitochondrion
  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • endoplasmic reticulum-Golgi intermediate compartment
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000331222
Coding exons
2
Length
30795
Individuals with no LoFs
125734
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125748
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.7662001721.160.00001081879
Missense (PolyPhen)5966.0720.89296755
Synonymous-2.3410276.01.340.00000519586
Loss of Function1.2258.950.5593.90e-786

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000880.000088rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Could play a role in cell proliferation during neuronal differentiation and in protection against cell death. {ECO:0000269|PubMed:19431184}.;
Disease
DISEASE: Ceroid lipofuscinosis, neuronal, 8 (CLN8) [MIM:600143]: A form of neuronal ceroid lipofuscinosis with onset in childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment patterns observed most often in neuronal ceroid lipofuscinosis type 8 comprise mixed combinations of granular, curvilinear, and fingerprint profiles. {ECO:0000269|PubMed:15024724, ECO:0000269|PubMed:16570191, ECO:0000269|PubMed:19201763, ECO:0000269|PubMed:19431184, ECO:0000269|PubMed:19807737, ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:26443629}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (CLN8NE) [MIM:610003]: A form of neuronal ceroid lipofuscinosis clinically characterized by epilepsy that presents between 5 and 10 years of age with frequent tonic-clonic seizures followed by progressive mental retardation. Visual loss is not a prominent feature. Intracellular accumulation of autofluorescent material results in curvilinear and granular profiles on ultrastructural analysis. {ECO:0000269|PubMed:10508524, ECO:0000269|PubMed:21990111}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.142
RVIS EVS
-0.14
RVIS percentile EVS
43.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.160

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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