SYNGAP1

synaptic Ras GTPase activating protein 1, the group of MicroRNA protein coding host genes|C2 and RasGAP domain containing

Basic information

Region (hg38): 6:33419661-33453689

Links

ENSG00000197283 ∙ NCBI:8831 ∙ OMIM:603384 ∙ HGNC:11497 ∙ Uniprot:Q96PV0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• intellectual disability, autosomal dominant 5 (Strong), mode of inheritance: AD
• myoclonic-astatic epilepsy (Supportive), mode of inheritance: Unknown
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• SYNGAP1-related developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• intellectual disability, autosomal dominant 5 (Strong), mode of inheritance: AD
• intellectual disability, autosomal dominant 5 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal dominant 5	AD	General	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	Neurologic	19196676; 23020937

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SYNGAP1 gene.

• Intellectual_disability,_autosomal_dominant_5 (1460 variants)
• not_provided (491 variants)
• Inborn_genetic_diseases (217 variants)
• not_specified (68 variants)
• SYNGAP1-related_disorder (51 variants)
• Complex_neurodevelopmental_disorder (18 variants)
• Intellectual_disability (13 variants)
• Seizure (7 variants)
• See_cases (6 variants)
• Global_developmental_delay (5 variants)
• Delayed_speech_and_language_development (3 variants)
• Motor_delay (2 variants)
• Atypical_behavior (2 variants)
• Neurodevelopmental_disorder (2 variants)
• Epileptic_encephalopathy (2 variants)
• Developmental_disorder (2 variants)
• Intellectual_disability,_autosomal_recessive_5 (1 variants)
• Stereotypic_movement_disorder (1 variants)
• Infantile_epilepsy_syndrome (1 variants)
• Aggressive_behavior (1 variants)
• SYNGAP1-related_encephalopathy (1 variants)
• Microcephaly (1 variants)
• Preauricular_skin_tag (1 variants)
• Hereditary_ataxia (1 variants)
• Marfanoid_habitus_and_intellectual_disability (1 variants)
• Downslanted_palpebral_fissures (1 variants)
• Generalized_hypotonia (1 variants)
• Pointed_chin (1 variants)
• Bulbous_tips_of_toes (1 variants)
• Wide_nasal_bridge (1 variants)
• Abnormal_sternum_morphology (1 variants)
• Ptosis (1 variants)
• Neurodevelopmental_delay (1 variants)
• High_forehead (1 variants)
• Cerebellar_ataxia (1 variants)
• Autosomal_dominant_epilepsy (1 variants)
• Infantile_epileptic_dyskinetic_encephalopathy (1 variants)
• Triangular_face (1 variants)
• Absent_speech (1 variants)
• Floppy_infant (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SYNGAP1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006772.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	3	3	7	377	6	396
missense	14	63	529	140	64	810
nonsense	72	16	3			91
start loss				1		1
frameshift	187	34	3	2		226
splice donor/acceptor (+/-2bp)	27	25	4	2	1	59
Total	303	141	546	522	71

Highest pathogenic variant AF is 0.000027364835

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SYNGAP1	protein_coding	protein_coding	ENST00000418600	19	33620

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125740	0	2	125742	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.60	351	796	0.441	0.0000537	8688
Missense in Polyphen		128	347.34	0.36852		3803
Synonymous	1.65	287	325	0.883	0.0000203	2808
Loss of Function	6.97	0	56.5	0.00	0.00000350	625

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000881	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR- mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term learning and memory deficits (By similarity). {ECO:0000250}.
• Disease: DISEASE: Mental retardation, autosomal dominant 5 (MRD5) [MIM:612621]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD5 patients show global developmental delay with delayed motor development, hypotonia, moderate-to- severe mental retardation, and severe language impairment. Epilepsy and autism can be present in some patients. {ECO:0000269|PubMed:19196676, ECO:0000269|PubMed:21076407, ECO:0000269|PubMed:21237447, ECO:0000269|PubMed:23161826, ECO:0000269|PubMed:23708187}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ras signaling pathway - Homo sapiens (human);Ras Signaling;Regulation of Ras family activation;Signal Transduction;Regulation of RAS by GAPs;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades (Consensus)

Recessive Scores

• pRec: 0.116

Intolerance Scores

• rvis_EVS: -1.15
• rvis_percentile_EVS: 6.23

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.755

Gene Damage Prediction

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

Zebrafish Information Network

• Gene name: syngap1b
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: dead

Gene ontology

• Biological process: MAPK cascade;Ras protein signal transduction;pattern specification process;visual learning;dendrite development;receptor clustering;regulation of MAPK cascade;negative regulation of neuron apoptotic process;positive regulation of GTPase activity;negative regulation of Ras protein signal transduction;regulation of synaptic plasticity;regulation of long-term neuronal synaptic plasticity;negative regulation of axonogenesis;regulation of synapse structure or activity;maintenance of postsynaptic specialization structure
• Cellular component: cytosol;plasma membrane;postsynaptic density;dendritic shaft;glutamatergic synapse
• Molecular function: GTPase activator activity;SH3 domain binding