SCYL2

protein-coding

SCY1 like pseudokinase 2, the group of SCY1 like pseudokinases|Armadillo like helical domain containing

Gene summary

The protein encoded by this gene associates with clathrin-coated complexes at the plasma membrane and with endocytic coated vesicles. The encoded protein phosphorylates the beta2 subunit of the plasma membrane adapter complex AP2 and interacts with clathrin, showing involvement in clathrin-dependent pathways between the trans-Golgi network and the endosomal system. In addition, this protein has a role in the Wnt signaling pathway by targeting frizzled 5 (Fzd5) for lysosomal degradation. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

MANE transcript

NM_017988.6

Inheritance

ClinVar variants

P:10U:122B:13

Top phenotype

Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr12:100,267,140-100,341,715

External References & Databases

Ensembl (ENSG00000136021)

Transcript & Mutation Effects

hg38 • Region Span ~74.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032903

Submitter: Labcorp Genetics (formerly Invitae)

arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032903

Submitter: PanelApp Australia

arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032903

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosumAR

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; 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: 31960134

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCYL2 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 116

not providedTotal: 10

Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosumTotal: 10

SCYL2-related disorderTotal: 9

not specifiedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017988.6. 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			3 clinvar	6 clinvar		9
missense			113 clinvar	6 clinvar	1 clinvar	120
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss						0
frameshift	1 clinvar	4 clinvar	3 clinvar			8
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	4	6	122	12	1	145

Highest pathogenic variant AF is 0.0000013692197

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017988.6	RefSeq	NP_060458.3	17	MANE Select
ENST00000360820.7	Ensembl	ENSP00000354061.2	17	MANE Select
NM_001317784.2	RefSeq	NP_001304713.1	17	Standard
NM_001330253.2	RefSeq	NP_001317182.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of receptor internalization
protein phosphorylation
endosome to lysosome transport
negative regulation of canonical Wnt signaling pathway
receptor internalization involved in canonical Wnt signaling pathway

Molecular Function

protein kinase activity
signaling receptor binding
protein binding
ATP binding

Cellular Component

Golgi apparatus
endosome membrane
clathrin-coated vesicle
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360820
Coding exons: 17
Length: 74585
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125747
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	389	465	0.837	0.0000217	6151
Missense (PolyPhen)		62	103.12	0.60126		1478
Synonymous	0.387	153	159	0.961	0.00000771	1734
Loss of Function	4.56	11	43.4	0.253	0.00000215	549

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of AP2-containing clathrin coated structures at the plasma membrane or of endocytic coated vesicles. According to PubMed:15809293, probable serine/threonine-protein kinase that phosphorylates, in vitro, the beta2-subunit of the plasma membrane adapter complex AP2 and other proteins in presence of poly-L- lysine. According to PubMed:16914521, has no detectable kinase activity in vitro. May regulate clathrin-dependent trafficking between the TGN and/or the endosomal system. {ECO:0000269|PubMed:15809293, ECO:0000269|PubMed:16914521}.;

Recessive Scores

pRec: 0.193

Intolerance Scores

LoFtool: 0.376
RVIS EVS: 0.04
RVIS percentile EVS: 57.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.924

Gene Damage Prediction

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