SCYL1

protein-coding

SCY1 like pseudokinase 1, the group of Armadillo like helical domain containing|SCY1 like pseudokinases

Gene summary

This gene encodes a transcriptional regulator belonging to the SCY1-like family of kinase-like proteins. The protein has a divergent N-terminal kinase domain that is thought to be catalytically inactive, and can bind specific DNA sequences through its C-terminal domain. It activates transcription of the telomerase reverse transcriptase and DNA polymerase beta genes. The protein has been localized to the nucleus, and also to the cytoplasm and centrosomes during mitosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

NTKL

MANE transcript

NM_020680.4

Inheritance

ClinVar variants

P:38U:162B:80

Top phenotype

Spinocerebellar ataxia, autosomal recessive 21

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr11:65,525,077-65,538,704

External References & Databases

Ensembl (ENSG00000142186)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: LiferaOmics

Genetic evidence – Published PMID: 29419818 – Family 1 – one proband (affected siblings counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown =no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 PMID: 29419818 – Family 2 – one proband (affected sibling counted under segregation). Case-level (biallelic non-LOF in AR model; homozygous missense; consanguinity unknown) = 0.1; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 2 total = 0.6 PMID: 29419818 – Family 3 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown → no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 3 total = 1.5 PMID: 29419818 – Family 4 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown = no −0.5 applied) = 1.5; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 4 total = 2.0 PMID: 29419818 – Family 5 – one proband. Case-level (biallelic non-LOF in AR model; homozygous missense; consanguinity unknown = no −0.5 applied) = 0.1; Segregation = 0; Case-control = 0 Family 5 total = 0.1 PMID: 29419818 total = 5.7 PMID: 26581903 – Family 1 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; compound heterozygous; consanguinity unknown = no −0.5 applied) = 1.5; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 2.0 PMID: 26581903 – Family 2 – one proband. Case-level (biallelic predicted null in AR model; compound heterozygous, each variant evaluated independently; consanguinity unknown = no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 3.0 PMID: 26581903 total = 5.5 PMID: 30258122 – Family 1 – one proband (affected relative counted under segregation). Case-level (biallelic non-LOF in AR model; consanguinity unknown = no −0.5 applied) = 1.0; Segregation (additional affected relative; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 30258122 total = 1.5 PMID: 33442927 – Family 1 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; compound heterozygous; consanguinity unknown → no =0.5 applied) = 1.5; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 2.0 PMID: 33442927 total = 2.0 PMID: 41142852 – Family 1 – one proband (Case-level (biallelic predicted null in AR model; homozygous canonical splice; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 PMID: 41142852 total = 1.0 PMID: 37644014 – Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous canonical splice NM_020680.4:c.1386+1G>T; consanguinity unknown → no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family F7600 total = 1.5 PMID: 37644014 total = 1.5 Published genetic evidence total = (raw 17.2, capped at 12.0) / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous canonical splice c.1386+1G>T; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (two siblings deceased from liver failure; no genotype = not scored) = 0; Case-control = 0 Family 1 total = 1.0 Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous nonsense c.1420C>T;p.Arg474Ter; non-consanguineous) = 1.5; Segregation = 0; Case-control = 0 Family 2 total = 1.5 Family 3 – one proband. Case-level (biallelic predicted null in AR model; homozygous canonical splice c.1386+1G>T; consanguinity unknown → no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 3 total = 1.5 Our cases total = 4.0 / 12 Total genetic evidence (published AR + our cases) Published genetic evidence (capped): 12.0 Our additional cases: 4.0 Total genetic evidence = 12.0 / 12 (cap applies) Experimental evidence – Published PMID: 29419818 – Functional alteration (patient-derived material/cells; supports SCYL1 deficiency and relevant cellular dysfunction) = 1.0 PMID: 26581903 – Non-human model organism (Scyl1 “mdf” mouse supporting neurodegeneration relevance) = 1.0 PMID: 26581903 – Functional alteration (patient fibroblasts; Golgi/trafficking abnormality consistent with mechanism) = 0.5 PMID: 33442927 – Functional alteration (patient fibroblasts; markedly reduced/absent SCYL1 protein) = 0.5 Gene function / biological plausibility (SCYL1 role in intracellular trafficking/COPI–Golgi pathways; consistent with hepato-neuro phenotype) = 0.5 Experimental evidence total = 3.5 / 6 Overall score Genetic evidence = 12.0 Experimental evidence = 3.5 Overall score = 15.5 / 18 First SCYL1 disease report: 2015 (PMID: 26581903) Multiple independent reports: 2018, 2019, 2021, 2023, 2024

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: Orphanet

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: Labcorp Genetics (formerly Invitae)

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: Ambry Genetics

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: G2P

acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014744

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 21AR

Manifestation: Gastrointestinal; Neurologic

Intervention: Gastrointestinal

Rationale: Individuals have been described with childhood-onset acute liver failure, and awareness may allow surveillance and prompt management

Refs: 26581903

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCYL1 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 138

not providedTotal: 121

SCYL1-related disorderTotal: 60

Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndromeTotal: 31

not specifiedTotal: 30

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020680.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	6 clinvar	59 clinvar		66
missense	2 clinvar	1 clinvar	144 clinvar	20 clinvar	1 clinvar	168
nonsense	6 clinvar	4 clinvar	1 clinvar			11
start loss	1 clinvar	1 clinvar				2
frameshift	10 clinvar	7 clinvar	2 clinvar			19
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	9 clinvar			14
Total	20	18	162	79	1	280

Highest pathogenic variant AF is 0.00003533832

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 180 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020680.4	RefSeq	NP_065731.3	18	MANE Select
ENST00000270176.10	Ensembl	ENSP00000270176.5	18	MANE Select
NM_001048218.2	RefSeq	NP_001041683.1	18	Standard
NM_001411022.1	RefSeq	NP_001397951.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in leukocytes - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
peptidyl-tyrosine phosphorylation

Molecular Function

DNA binding
protein tyrosine kinase activity
ATP binding
cadherin binding

Cellular Component

nucleus
cytoplasm
endoplasmic reticulum-Golgi intermediate compartment
Golgi apparatus
cis-Golgi network

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270176
Coding exons: 18
Length: 13628
Individuals with no LoFs: 124778
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 124829
p: 0.000204

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.33	405	488	0.830	0.0000299	5219
Missense (PolyPhen)		98	127.28	0.76996		1340
Synonymous	-0.0597	208	207	1.01	0.0000137	1624
Loss of Function	3.25	20	43.0	0.466	0.00000233	448

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00045	0.00042	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00016	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates COPI-mediated retrograde protein traffic at the interface between the Golgi apparatus and the endoplasmic reticulum (PubMed:18556652). Involved in the maintenance of the Golgi apparatus morphology (PubMed:26581903). Has no detectable kinase activity in vitro (PubMed:18556652). {ECO:0000269|PubMed:18556652, ECO:0000269|PubMed:26581903}.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 21 (SCAR21) [MIM:616719]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR21 is characterized by cerebellar atrophy and ataxia with onset in early childhood. Patients also manifest recurrent episodes of liver failure, hepatic fibrosis and a peripheral neuropathy. {ECO:0000269|PubMed:26581903}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.678
RVIS EVS: 0.47
RVIS percentile EVS: 78.83

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.760

Gene Damage Prediction

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