CERKL

protein-coding

ceramide kinase like

Gene summary

This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

Previous symbols:

RP26

MANE transcript

NM_201548.5

Inheritance

AR, AD

ClinVar variants

P:216U:289B:274

Top phenotype

Retinitis pigmentosa 26

gnomAD constraint

pLI —, LoF o/e 1.16

Max pathogenic AF

—

Genomic locus

chr2:181,535,041-181,680,665

External References & Databases

Ensembl (ENSG00000188452)

Transcript & Mutation Effects

hg38 • Region Span ~145.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012024

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 26DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012024

Submitter: Natera

retinitis pigmentosa 26DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012024

Submitter: G2P

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

CERKL-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800401

Submitter: ClinGen

*CERKL* was first reported in relation to autosomal recessive retinitis pigmentosa in 2004 (Tuson et al., PMID: 14681825). Several variants (nonsense, frameshift, canonical splicing) that have been reported are included in this curation. 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 LOF. Because of the broad spectrum of potential phenotypes, these cases with causal variants in *CERKL* have been curated under the inclusive disease name *CERKL*-related retinopathy (MONDO:0800401). This gene-disease relationship is also supported by animal models (PMIDs: 28398482, 32658961). In summary, *CERKL* is definitively associated with *CERKL*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).

Clinical Genomic Database (CGD)

Retinitis pigmentosa 26AR

Manifestation: 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: 14681825

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CERKL variants in ClinVar

20 Conditions Cataloged

not providedTotal: 894

Retinitis pigmentosa 26Total: 279

Inborn genetic diseasesTotal: 77

not specifiedTotal: 69

Retinitis pigmentosaTotal: 63

Retinal dystrophyTotal: 55

CERKL-related disordersTotal: 52

CERKL-related disorderTotal: 43

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_201548.5. 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			12 clinvar	251 clinvar		263
missense	1 clinvar	24 clinvar	263 clinvar	22 clinvar	1 clinvar	311
nonsense	24 clinvar	26 clinvar	3 clinvar			53
start loss	3 clinvar	1 clinvar				4
frameshift	43 clinvar	45 clinvar	8 clinvar			96
splice donor/acceptor (+/-2bp)	4 clinvar	45 clinvar	3 clinvar			52
Total	75	141	289	273	1	779

Highest pathogenic variant AF is 0.0005930632

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_201548.5	RefSeq	NP_963842.1	13	MANE Select
ENST00000410087.8	Ensembl	ENSP00000386725.3	13	MANE Select
NM_001030311.3	RefSeq	NP_001025482.1	14	Standard
NM_001030312.3	RefSeq	NP_001025483.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cerkl	Danio rerio	Structure: retinal rod cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

cerkl

Danio rerio

Structure: retinal rod cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

phosphorylation
sphingolipid biosynthetic process

Molecular Function

NAD+ kinase activity
sphingolipid binding

Cellular Component

photoreceptor outer segment
photoreceptor inner segment
nucleus
nucleolus
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339098
Coding exons: 14
Length: 143990
Individuals with no LoFs: 125553
Homozygous LoFs: 0
Heterozygous LoFs: 195
Defined: 125748
p: 0.000776

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.266	316	303	1.04	0.0000148	3626
Missense (PolyPhen)		83	92.682	0.89553		1137
Synonymous	0.173	107	109	0.979	0.00000549	1061
Loss of Function	-0.797	34	29.3	1.16	0.00000147	352

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00076	0.00075	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00055	0.00054	rare
Finnish	0.0013	0.0013	notable
European (Non-Finnish)	0.00089	0.00086	rare
South Asian	0.00079	0.00078	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has no detectable ceramide-kinase activity. Overexpression of CERKL protects cells from apoptosis in oxidative stress conditions. {ECO:0000269|PubMed:15708351, ECO:0000269|PubMed:19158957}.;
Disease: DISEASE: Retinitis pigmentosa 26 (RP26) [MIM:608380]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:14681825, ECO:0000269|PubMed:18978954}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0976

Intolerance Scores

LoFtool: 0.988
RVIS EVS: 0.71
RVIS percentile EVS: 85.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.224

Gene Damage Prediction

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