IQSEC2

protein-coding

IQ motif and Sec7 domain ArfGEF 2, the group of IQSEC ArfGEF family

Gene summary

This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

Previous symbols:

MRX1
MRX78
MRX18

MANE transcript

NM_001111125.3

Inheritance

ClinVar variants

P:251U:608B:508

Top phenotype

Intellectual developmental disorder, X-linked 1

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:53,225,828-53,321,350

External References & Databases

Ensembl (ENSG00000124313)

Transcript & Mutation Effects

hg38 • Region Span ~95.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010656

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010656

Submitter: PanelApp Australia

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*IQSEC2* was first reported in relation to X-linked complex neurodevelopmental disorder (specifically intellectual disability) in 1988 (Suthers et al., PMID: 3177466). Affected individuals, including both males and females, typically have intellectual disability with variable seizures, autistic traits, and psychiatric problems. Males are generally more severely affected compared with females. Eight variants (nonsense and frameshift) that have been reported in eight probands from one publication with a large patient cohort (PMID: 30206421) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. To date, at least 70 variants in *IQSEC2* have been reported in patients (PMID: 30328660) and 47 unique variants in *IQSEC2* have been classified as pathogenic in ClinVar. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal and cell culture models. In summary, there is definitive evidence supporting the relationship between *IQSEC2* iand X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 5, 2019 (SOP Version 6).

severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018347

Submitter: Orphanet

intellectual developmental disorder, X-linked 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010656

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010656

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 1XL

Manifestation: Neurologic

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: 7943039; 3177466; 20473311

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IQSEC2 variants in ClinVar

24 Conditions Cataloged

Intellectual disability, X-linked 1Total: 1107

not providedTotal: 481

Inborn genetic diseasesTotal: 159

not specifiedTotal: 133

IQSEC2-related disorderTotal: 67

NEURODEVELOPMENTAL DISORDER, X-LINKED, WITH POOR OR ABSENT SPEECH AND BEHAVIORAL ABNORMALITIESTotal: 11

Intellectual disabilityTotal: 8

See casesTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001111125.3. 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		2 clinvar	19 clinvar	348 clinvar	30 clinvar	399
missense	11 clinvar	27 clinvar	570 clinvar	110 clinvar	20 clinvar	738
nonsense	49 clinvar	19 clinvar	1 clinvar			69
start loss						0
frameshift	88 clinvar	29 clinvar	4 clinvar			121
splice donor/acceptor (+/-2bp)	11 clinvar	15 clinvar	14 clinvar			40
Total	159	92	608	458	50	1367

Highest pathogenic variant AF is 0.000026510592

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001111125.3	RefSeq	NP_001104595.1	15	MANE Select
ENST00000642864.1	Ensembl	ENSP00000495726.1	15	MANE Select
NM_001243197.2	RefSeq	NP_001230126.1	3	MANE Plus Clinical
NM_001410736.1	RefSeq	NP_001397665.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)

Biological Process

actin cytoskeleton organization
regulation of ARF protein signal transduction
modulation of chemical synaptic transmission
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane

Molecular Function

ARF guanyl-nucleotide exchange factor activity

Cellular Component

cytoplasm
Schaffer collateral - CA1 synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396435
Coding exons: 15
Length: 88465
Individuals with no LoFs: 124418
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124419
p: 0.00000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.19	241	598	0.403	0.0000515	9587
Missense (PolyPhen)		48	184.28	0.26047		2482
Synonymous	1.91	210	248	0.845	0.0000204	3186
Loss of Function	5.37	1	35.6	0.0281	0.00000282	577

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000089	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Is a guanine nucleotide exchange factor for the ARF GTP- binding proteins. {ECO:0000269|PubMed:26793055}.;

Recessive Scores

pRec: 0.0922

Intolerance Scores

LoFtool: 0.228
RVIS EVS: -0.52
RVIS percentile EVS: 21.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.328

Gene Damage Prediction

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