GeneBe

CLN6

protein-coding

CLN6 transmembrane ER protein

Gene summary

This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function. [provided by RefSeq, Oct 2008]

MANE transcript

NM_017882.3

Inheritance

AR

ClinVar variants

P:153U:201B:238

Top phenotype

Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6B

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr15:68,206,992-68,257,211

External References & Databases

Ensembl (ENSG00000128973)NCBI Gene (54982)OMIM (606725)HGNC:2077GenCCUniProt (Q9NWW5)AlphaFoldClinVar (CLN6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~50.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ceroid lipofuscinosis, neuronal, 6B (Kufs type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008768

Submitter: Genomics England PanelApp

ceroid lipofuscinosis, neuronal, 6ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011144

Submitter: G2P

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

CLN6 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) as early as 2002 (Gao et al., Wheeler et al., PMIDs: 11791207, 11727201). Clinical features of NCL include seizures, developmental delay, behavioral changes, vision loss, dementia, and movement and language difficulties. While NCL may be caused by at least a dozen genes in the CLN family (PMID: 26026925), age of onset of CLN6-related NCL varies from late infantile to teenage or adult years, with loss of function variants occurring more frequently in probands with earlier disease onset (PMID: 30561534). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern, and several variants were shared between the late infantile and adult onset conditions. Therefore, the following disease entities have been lumped into one disease entity: NCL6 (MIM #601780) and NCL6, Kufs type, adult onset (MIM #204300). More than 100 variants (including missense, in-frame indel, nonsense, frameshift, splice site, and large deletions) have been reported in humans. Eleven variants in 8 probands reported in 5 publications are included in this curation (PMID: 19135028, 11791207, 11727201, 12673792, 30561534). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function (PMID: 11791207). This gene-disease association is also supported by animal models (murine, canine, feline, and ovine), expression studies, and protein interaction with CLN8, a gene which has also been definitively associated with NCL (PMID: 32597833, 22012656, 24223841, 31331814, 21234413, 32518081, 17046213). In summary, CLN6 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 curation was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 12/1/20 (SOP Version 8).

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: Natera

ceroid lipofuscinosis, neuronal, 6ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011144

Submitter: Labcorp Genetics (formerly Invitae)

ceroid lipofuscinosis, neuronal, 6ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011144

Submitter: Genomics England PanelApp

ceroid lipofuscinosis, neuronal, 6ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011144

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

ceroid lipofuscinosis, neuronal, 6B (Kufs type)DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008768

Submitter: G2P

ceroid lipofuscinosis, neuronal, 6ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011144

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6BAR

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: 13822848; 5478271; 760366; 3284607; 7668317; 10929274; 11791207; 11727201; 15965709; 15996215; 19520283; 21549341; 21990111; 22883287; 23180398; 23735787; 30561534Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLN6 variants in ClinVar

17 Conditions Cataloged
Neuronal ceroid lipofuscinosisTotal: 635
not providedTotal: 170
Ceroid lipofuscinosis, neuronal, 6ATotal: 119
not specifiedTotal: 93
Inborn genetic diseasesTotal: 69
Ceroid lipofuscinosis, neuronal, 6B (Kufs type)Total: 62
CLN6-related disorderTotal: 27
Adult neuronal ceroid lipofuscinosisTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017882.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
221
clinvar
2
clinvar
 224
missense
6
clinvar
42
clinvar
196
clinvar
14
clinvar
1
clinvar
 259
nonsense
16
clinvar
11
clinvar
1
clinvar
 28
start loss
3
clinvar
2
clinvar
 5
frameshift
33
clinvar
20
clinvar
2
clinvar
 55
splice donor/acceptor (+/-2bp)
2
clinvar
18
clinvar
1
clinvar
 21
Total60932012353592

Highest pathogenic variant AF is 0.00007322608

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017882.3RefSeqNP_060352.17MANE Select
ENST00000249806.11EnsemblENSP00000249806.57MANE Select
NM_001411068.1RefSeqNP_001397997.17Standard
ENST00000538696.5EnsemblENSP00000445770.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • ganglioside metabolic process
  • lysosome organization
  • lysosomal lumen acidification
  • visual perception
  • cholesterol metabolic process

Molecular Function

  • protein binding
  • protein homodimerization activity

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum lumen
  • endoplasmic reticulum membrane
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000249806
Coding exons
7
Length
50220
Individuals with no LoFs
125706
Homozygous LoFs
0
Heterozygous LoFs
42
Defined
125748
p
0.000167
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.009221761761.000.00001182031
Missense (PolyPhen)6377.4510.81342932
Synonymous-2.5310274.31.370.00000525633
Loss of Function1.23812.70.6285.62e-7149

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000520.00052rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.000140.00014rare
South Asian0.000160.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease
DISEASE: Ceroid lipofuscinosis, neuronal, 6 (CLN6) [MIM:601780]: A form of neuronal ceroid lipofuscinosis. 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 6 comprise mixed combinations of granular, curvilinear, and fingerprint profiles. {ECO:0000269|PubMed:11727201, ECO:0000269|PubMed:11791207, ECO:0000269|PubMed:12673792, ECO:0000269|PubMed:12815591, ECO:0000269|PubMed:19201763, ECO:0000269|PubMed:21990111, ECO:0000269|Ref.2}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ceroid lipofuscinosis, neuronal, 4A (CLN4A) [MIM:204300]: An adult-onset neuronal ceroid lipofuscinosis. 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. CLN4A has no visual involvement and is characterized by progressive myoclonic epilepsy. {ECO:0000269|PubMed:21549341}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.205

Intolerance Scores

LoFtool
0.171
RVIS EVS
-0.07
RVIS percentile EVS
48.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.599

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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