ITSN2

protein-coding

intersectin 2, the group of EF-hand domain containing|C2 domain containing|Dbl family Rho GEFs

Gene summary

This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersectin 2 is thought to regulate the formation of clathrin-coated vesicles and also may function in the induction of T cell antigen receptor (TCR) endocytosis. [provided by RefSeq, Jan 2017]

Previous symbols:

SH3D1B

MANE transcript

NM_006277.3

Inheritance

ClinVar variants

U:310B:88

Top phenotype

nephrotic syndrome

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr2:24,202,864-24,360,536

External References & Databases

Ensembl (ENSG00000198399)

Transcript & Mutation Effects

hg38 • Region Span ~157.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005377

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITSN2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 219

not providedTotal: 194

ITSN2-related disorderTotal: 82

Landau-Kleffner syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006277.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	57 clinvar	7 clinvar	71
missense			287 clinvar	17 clinvar	6 clinvar	310
nonsense			2 clinvar			2
start loss			2 clinvar			2
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			11 clinvar	1 clinvar		12
Total	0	0	310	75	13	398

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006277.3	RefSeq	NP_006268.2	39	MANE Select
ENST00000355123.9	Ensembl	ENSP00000347244.4	39	MANE Select
NM_001348181.2	RefSeq	NP_001335110.1	38	Standard
NM_001348182.2	RefSeq	NP_001335111.1	38	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
TCR
Clathrin-mediated endocytosis
EGFR1

Biological Process

endocytosis
positive regulation of signal transduction
viral process
regulation of Rho protein signal transduction
positive regulation of dendrite extension

Molecular Function

SH3/SH2 adaptor activity
Rho guanyl-nucleotide exchange factor activity
calcium ion binding
protein binding

Cellular Component

cytoplasm
centrosome
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355123
Coding exons: 39
Length: 157851
Individuals with no LoFs: 125599
Homozygous LoFs: 1
Heterozygous LoFs: 148
Defined: 125748
p: 0.000593

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	788	881	0.894	0.0000479	11073
Missense (PolyPhen)		90	135.5	0.66421		1656
Synonymous	-0.603	333	319	1.04	0.0000168	3129
Loss of Function	6.00	41	108	0.378	0.00000587	1276

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00086	0.00084	rare
Ashkenazi Jewish	0.00042	0.00040	rare
East Asian	0.00055	0.00054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00065	0.00063	rare
South Asian	0.00074	0.00072	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery. May regulate the formation of clathrin-coated vesicles (CCPs). Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000269|PubMed:19458185, ECO:0000269|PubMed:22648170, ECO:0000269|PubMed:23999003}.;

Recessive Scores

pRec: 0.183

Intolerance Scores

LoFtool: 0.926
RVIS EVS: -0.51
RVIS percentile EVS: 21.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.634

Gene Damage Prediction

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