Human Gene Module / Chromosome 16 / GRIN2A

GRIN2Aglutamate receptor, ionotropic, N-methyl D-aspartate 2A

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
15 / 69
Rare Variants / Common Variants
205 / 5
EAGLE Score
3.6
Limited Learn More
Aliases
GRIN2A, NR2A,  NMDAR2A
Associated Syndromes
Pediatric Acute-Onset Neuropsychiatric Syndrome (P
Chromosome Band
16p13.2
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Molecular Function

This gene encodes a member of the glutamate-gated ion channel protein family. The encoded protein is an N-methyl-D-aspartate (NMDA) receptor subunit. NMDA receptors are both ligand-gated and voltage-dependent, and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades. Disruption of this gene is associated with focal epilepsy and speech disorder with or without cognitive disability.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIN2A (69 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT Barnby G , et al. (2005) Yes -
2 Recent Recommendation Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons Losonczy A and Magee JC (2006) No -
3 Recent Recommendation Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses Dufour F , et al. (2006) No -
4 Recent Recommendation Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors Izumi Y , et al. (2006) No -
5 Recent Recommendation NMDA receptor function: subunit composition versus spatial distribution Khr G (2006) No -
6 Support Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes Endele S , et al. (2010) No ID
7 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
8 Support Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism Lesca G , et al. (2012) No ADHD
9 Support Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia Tarabeux J , et al. (2011) Yes -
10 Support Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) No Epilepsy, ASD
11 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
12 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
13 Recent Recommendation GRIN2A mutations cause epilepsy-aphasia spectrum disorders Carvill GL , et al. (2013) No -
14 Recent Recommendation Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes Lemke JR , et al. (2013) No DD, ID
15 Recent Recommendation GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction Lesca G , et al. (2013) No -
16 Support Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation Venkateswaran S , et al. (2014) No -
17 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities Zhang Y , et al. (2015) No -
18 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms D'Gama AM , et al. (2015) Yes -
19 Recent Recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease Johnson MR , et al. (2015) No -
20 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
21 Recent Recommendation Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains Swanger SA , et al. (2016) No ASD, epilepsy/seizures
22 Support Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology Ogden KK , et al. (2017) No -
23 Support Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs von Stlpnagel C , et al. (2017) No DD, ID
24 Support Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy Chen W , et al. (2017) No -
25 Support A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia Gao K , et al. (2017) No -
26 Recent Recommendation Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue Addis L , et al. (2017) No -
27 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
28 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment Chen XS , et al. (2017) No -
29 Support Functional assessment of the NMDA receptor variant GluN2A R586K Marwick KFM , et al. (2017) No -
30 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
31 Support Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit Sibarov DA , et al. (2017) No -
32 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test Lionel AC , et al. (2017) No -
33 Highly Cited Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain Garthwaite J , et al. (1988) No -
34 Support Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility Yu Y , et al. (2018) Yes -
35 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
36 Support A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder Fernndez-Marmiesse A , et al. (2018) No Movement disorder
37 Recent recommendation GRIN2A-related disorders: genotype and functional consequence predict phenotype Strehlow V , et al. (2018) No -
38 Support De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases Li J , et al. (2019) No -
39 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism Breuss MW , et al. (2019) Yes -
40 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
41 Support - Hildebrand MS et al. (2020) No DD
42 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes ID, epilepsy/seizures
43 Support - Ariadna Amador et al. (2020) No -
44 Support Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression Yin J et al. (2020) Yes Developmental regression, epilepsy/seizures
45 Support An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKII? Phosphorylation of GluN2A and NMDA Receptor Trafficking Mota Vieira M et al. (2020) No -
46 Support - Zou D et al. (2021) No -
47 Support - Yong XLH et al. (2021) No -
48 Support - Mangano GD et al. (2022) Yes ADD
49 Support - Elmasri M et al. (2022) No DD, ID
50 Support - Hieu NLT et al. (2022) No -
51 Recent Recommendation - Singh T et al. (2022) No -
52 Support - Chuan Z et al. (2022) No DD
53 Support - Trifiletti R et al. (2022) No Learning disability
54 Support - Krgovic D et al. (2022) Yes ADHD, DD, ID
55 Support - Zhou X et al. (2022) Yes -
56 Recent Recommendation - Weinschutz Mendes H et al. (2023) Yes -
57 Support - Wang J et al. (2023) Yes -
58 Support - Bartolomaeus T et al. (2023) No -
59 Support - Chad R Camp et al. (2023) No -
60 Support - Marketa Wayhelova et al. (2024) No -
61 Support - Magdalena Badura-Stronka et al. (2024) No -
62 Support - Purvi Majethia et al. (2024) No ADHD
63 Support - Tamam Khalaf et al. (2024) No -
64 Support - Yuchen Xu et al. (2024) No ASD
65 Support - Ruohao Wu et al. (2024) No -
66 Support - Alistair T Pagnamenta et al. (2024) No -
67 Support - Hosneara Akter et al. () No -
68 Support - Paola Granata et al. (2024) Yes -
69 Highly Cited Developmental and regional expression in the rat brain and functional properties of four NMDA receptors Monyer H , et al. (1994) No -
Rare Variants   (205)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 30544257 Strehlow V , et al. (2018)
- - copy_number_loss De novo - - 30544257 Strehlow V , et al. (2018)
- - copy_number_loss Unknown - - 30544257 Strehlow V , et al. (2018)
- - copy_number_loss De novo - Unknown 22738016 Lesca G , et al. (2012)
- - copy_number_gain Unknown - Unknown 23933819 Lemke JR , et al. (2013)
- - copy_number_loss Unknown - Unknown 23933819 Lemke JR , et al. (2013)
- - copy_number_gain Unknown - - 28109652 von Stlpnagel C , et al. (2017)
- - copy_number_loss Familial Maternal - 30544257 Strehlow V , et al. (2018)
- - copy_number_loss Familial Paternal - 30544257 Strehlow V , et al. (2018)
- - copy_number_loss Familial - Multiplex 30544257 Strehlow V , et al. (2018)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
c.982G>T p.Glu328Ter stop_gained Unknown - - 35813072 Krgovic D et al. (2022)
c.3190A>G p.Thr1064Ala missense_variant - - - 20890276 Endele S , et al. (2010)
c.428C>T p.Thr143Ile missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.418C>G p.Pro140Ala missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.446C>T p.Ala149Val missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.2765C>T p.Ala922Val missense_variant - - - 22833210 Tarabeux J , et al. (2011)
c.415-2A>G - splice_site_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1323A>C p.Lys441Asn missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.1770A>C p.Lys590Asn missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.2650G>A p.Asp884Asn missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.2890C>G p.Gln964Glu missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.165G>A p.Trp55Ter stop_gained Familial - - 30544257 Strehlow V , et al. (2018)
c.500G>A p.Trp167Ter stop_gained De novo - - 30544257 Strehlow V , et al. (2018)
c.1007+1G>A - splice_site_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1497+1G>C - splice_site_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2007+2dup - splice_site_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.2008-1G>T - splice_site_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.2518C>T p.Leu840Phe missense_variant Familial - - 29317596 Yu Y , et al. (2018)
c.2627T>C p.Ile876Thr missense_variant Familial - - 29317596 Yu Y , et al. (2018)
c.3386A>G p.His1129Arg missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.3059C>G p.Ser1020Cys missense_variant Unknown - - 32477112 Lee J et al. (2020)
c.1532C>T p.Ser511Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1948G>T p.Ala650Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2084G>A p.Arg695Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2257G>A p.Gly753Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.1036A>T p.Lys346Ter stop_gained De novo - - 30544257 Strehlow V , et al. (2018)
c.1613C>G p.Ser538Ter stop_gained De novo - - 30544257 Strehlow V , et al. (2018)
c.1818G>A p.Trp606Ter stop_gained De novo - - 30544257 Strehlow V , et al. (2018)
c.2998G>A p.Val1000Met missense_variant Familial - - 29317596 Yu Y , et al. (2018)
c.3721C>T p.Arg1241Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1007+1G>A - splice_site_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1543A>C p.Asn515His missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
G>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.28C>A p.Leu10Met missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.1845C>A p.Asn615Lys missense_variant De novo - - 20890276 Endele S , et al. (2010)
c.2329C>G p.Leu777Val missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.568A>G p.Thr190Ala missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
- - copy_number_loss Familial Maternal Multiplex 30544257 Strehlow V , et al. (2018)
c.3228C>G p.Asn1076Lys missense_variant Unknown - - 20890276 Endele S , et al. (2010)
c.4204C>T p.Arg1402Trp missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.594G>A p.Trp198Ter stop_gained Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.1655C>G p.Pro552Arg missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
c.1945C>G p.Leu649Val missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
c.2050A>G p.Thr684Ala missense_variant De novo - - 28771251 Lionel AC , et al. (2017)
c.1661G>C p.Ser554Thr missense_variant De novo - - 35217385 Mangano GD et al. (2022)
- - copy_number_gain Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
c.904G>T p.Ala302Ser missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
C>T p.Met788Ile missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2054T>C p.Val685Ala missense_variant Unknown - - 27839871 Swanger SA , et al. (2016)
c.2450T>C p.Met817Thr missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.1232T>A p.Leu411Gln missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1492G>A p.Gly498Ser missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1552C>T p.Arg518Cys missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1552C>T p.Arg518Cys missense_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1553G>A p.Arg518His missense_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1592C>T p.Thr531Met missense_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1595G>T p.Gly532Val missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1642G>C p.Ala548Pro missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1655C>G p.Pro552Arg missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1832T>A p.Leu611Gln missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1841A>G p.Asn614Ser missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1903G>A p.Ala635Thr missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1930A>G p.Ser644Gly missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1936A>G p.Thr646Ala missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1943A>G p.Asn648Ser missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1945C>G p.Leu649Val missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1959G>A p.Met653Ile missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1961T>C p.Ile654Thr missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2050A>G p.Thr684Ala missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2084G>A p.Arg695Gln missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2138T>G p.Val713Gly missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2146G>A p.Ala716Thr missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2191G>A p.Asp731Asn missense_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.2197G>A p.Ala733Thr missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2427C>A p.Ser809Arg missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2449A>G p.Met817Val missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2449A>G p.Met817Val missense_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.2450T>C p.Met817Thr missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2450T>G p.Met817Arg missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2453C>A p.Ala818Glu missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1818G>A p.Trp606Ter stop_gained Unknown - - 28109652 von Stlpnagel C , et al. (2017)
c.2407G>T p.Glu803Ter stop_gained De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.4375A>G p.Ser1459Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2450T>C p.Met817Thr missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.602A>G p.Gln201Arg missense_variant Familial Maternal - 34145886 Zou D et al. (2021)
c.2191G>A p.Asp731Asn missense_variant De novo - Simplex 28182669 Gao K , et al. (2017)
c.1007+1G>A - splice_site_variant De novo - Multiplex 31873310 Breuss MW , et al. (2019)
c.3578T>G p.Leu1193Trp missense_variant Unknown - - 35773312 Trifiletti R et al. (2022)
c.3174C>A p.His1058Gln missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1651+1del - splice_site_variant Familial Maternal - 30544257 Strehlow V , et al. (2018)
c.594G>A p.Trp198Ter stop_gained Unknown - Multiplex 30544257 Strehlow V , et al. (2018)
c.2899G>C p.Val967Leu missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.1642G>A p.Ala548Thr missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.1954T>G p.Phe652Val missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.2007G>T p.Lys669Asn missense_variant Unknown - Simplex 23933820 Lesca G , et al. (2013)
c.2081T>C p.Ile694Thr missense_variant De novo - Simplex 23933820 Lesca G , et al. (2013)
c.2191G>A p.Asp731Asn missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.2493C>A p.Ser831Arg missense_variant De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.728C>T p.Ala243Val missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.869C>T p.Ala290Val missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.487C>T p.Gln163Ter stop_gained Familial - Multiplex 30544257 Strehlow V , et al. (2018)
c.4307A>G p.Asn1436Ser missense_variant Familial - - 39654053 Paola Granata et al. (2024)
- - copy_number_loss Familial Paternal Multiplex 38321498 Marketa Wayhelova et al. (2024)
c.3827C>G p.Ala1276Gly missense_variant Unknown - Unknown 23933820 Lesca G , et al. (2013)
- p.phe670fs copy_number_loss Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.2095C>T p.Pro699Ser missense_variant De novo - Simplex 23933819 Lemke JR , et al. (2013)
c.1108C>T p.Arg370Trp missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2140G>A p.Glu714Lys missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2179G>A p.Ala727Thr missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2314A>G p.Lys772Glu missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.2927A>G p.Asn976Ser missense_variant Unknown - Unknown 23933819 Lemke JR , et al. (2013)
c.1924C>A p.Leu642Met missense_variant De novo - Simplex 38538865 Yuchen Xu et al. (2024)
c.1925T>G p.Leu642Arg missense_variant De novo - Simplex 38538865 Yuchen Xu et al. (2024)
c.1930A>G p.Ser644Gly missense_variant De novo - Simplex 38538865 Yuchen Xu et al. (2024)
c.1936A>G p.Thr646Ala missense_variant De novo - Simplex 38538865 Yuchen Xu et al. (2024)
c.1895C>T p.Ser632Phe missense_variant Unknown - Unknown 38538865 Yuchen Xu et al. (2024)
c.1915G>A p.Val639Ile missense_variant Unknown - Unknown 38538865 Yuchen Xu et al. (2024)
c.1937C>G p.Thr646Arg missense_variant Unknown - Unknown 38538865 Yuchen Xu et al. (2024)
c.1943A>G p.Asn648Ser missense_variant De novo - Unknown 38538865 Yuchen Xu et al. (2024)
c.1948G>T p.Ala650Ser missense_variant De novo - Unknown 38538865 Yuchen Xu et al. (2024)
c.1957A>G p.Met653Val missense_variant De novo - Unknown 38538865 Yuchen Xu et al. (2024)
c.1913C>T p.Ala638Val missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1841A>G p.Asn614Ser missense_variant De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.1936A>G p.Thr646Ala missense_variant De novo - - 28109652 von Stlpnagel C , et al. (2017)
c.2332G>C p.Ala778Pro missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2855A>G p.Lys952Arg missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2650G>A p.Asp884Asn missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2197G>A p.Ala733Thr missense_variant De novo - Simplex 35217385 Mangano GD et al. (2022)
c.3751G>A p.Asp1251Asn missense_variant Familial Paternal - 23933820 Lesca G , et al. (2013)
c.1757G>A p.Arg586Lys missense_variant Familial Maternal - 20890276 Endele S , et al. (2010)
c.1306T>C p.Cys436Arg missense_variant De novo - Multiplex 23933819 Lemke JR , et al. (2013)
c.3120G>C p.Glu1040Asp missense_variant Unknown - Unknown 32277047 Chevarin M et al. (2020)
c.2902G>A p.Ala968Thr missense_variant De novo - Simplex 22833210 Tarabeux J , et al. (2011)
- - copy_number_loss Familial Paternal Multi-generational 30544257 Strehlow V , et al. (2018)
c.2007+1G>A - splice_site_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.627del p.Phe210LeufsTer10 frameshift_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2140del p.Glu714ArgfsTer7 frameshift_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2408del p.Glu803GlyfsTer5 frameshift_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.3669C>T p.Thr1223= synonymous_variant De novo - Simplex 22833210 Tarabeux J , et al. (2011)
c.2007+1G>A - splice_site_variant Familial Paternal - 28109652 von Stlpnagel C , et al. (2017)
c.1592C>T p.Thr531Met missense_variant Familial Maternal - 30544257 Strehlow V , et al. (2018)
c.1692del p.Met564IlefsTer8 frameshift_variant Familial - - 30544257 Strehlow V , et al. (2018)
c.1362del p.Lys454AsnfsTer11 frameshift_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.2253dup p.Ser752GlufsTer34 frameshift_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.1946_1947delinsCT p.Leu649Pro missense_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2077A>G p.Asn693Asp missense_variant De novo - Simplex 37460657 Bartolomaeus T et al. (2023)
c.1001T>A p.Leu334Ter stop_gained Familial Paternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2829C>G p.Tyr943Ter stop_gained Familial Paternal Multiplex 23933819 Lemke JR , et al. (2013)
c.551T>G p.Ile184Ser missense_variant Familial Maternal Simplex 23933820 Lesca G , et al. (2013)
c.3014A>G p.Lys1005Arg missense_variant Familial Paternal - 32345733 Hildebrand MS et al. (2020)
c.2449A>G p.Met817Val missense_variant De novo - Simplex 24903190 Venkateswaran S , et al. (2014)
c.2191G>A p.Asp731Asn missense_variant Familial Maternal Simplex 23933820 Lesca G , et al. (2013)
c.2797G>A p.Asp933Asn missense_variant Familial Paternal Simplex 23933820 Lesca G , et al. (2013)
c.547T>A p.Phe183Ile missense_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.1007+1G>A - splice_site_variant Unknown Not maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.1007+1G>A p.? splice_site_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
- - translocation Familial Maternal & paternal Multi-generational 20890276 Endele S , et al. (2010)
c.1007+1G>A p.? splice_site_variant Unknown - Multi-generational 23933819 Lemke JR , et al. (2013)
c.2441T>C p.Ile814Thr missense_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.883G>A p.Gly295Ser missense_variant Unknown Not maternal Simplex 23933820 Lesca G , et al. (2013)
c.1447G>A p.Gly483Arg missense_variant Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.1510C>T p.Arg504Trp missense_variant Familial Maternal Multiplex 23933820 Lesca G , et al. (2013)
c.1553G>A p.Arg518His missense_variant Familial Paternal Multiplex 23933820 Lesca G , et al. (2013)
c.692G>A p.Cys231Tyr missense_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.176_177insAGGC p.Ala60GlyfsTer79 frameshift_variant De novo - - 30544257 Strehlow V , et al. (2018)
c.2113A>G p.Met705Val missense_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2200G>C p.Val734Leu missense_variant Familial Paternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2710A>T p.Ile904Phe missense_variant Familial Paternal Multiplex 23933819 Lemke JR , et al. (2013)
c.1686del p.Phe562LeufsTer2 frameshift_variant Familial Paternal - 30544257 Strehlow V , et al. (2018)
c.1123-2A>G - splice_site_variant Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.1592C>T p.Thr531Met missense_variant Familial Maternal Multiplex 23933818 Carvill GL , et al. (2013)
c.2T>C p.Met1? initiator_codon_variant Familial Paternal Multiplex 23933818 Carvill GL , et al. (2013)
c.652C>T p.Gln218Ter stop_gained Familial Maternal Multi-generational 20890276 Endele S , et al. (2010)
c.2341_2343delinsAT p.Gln781IlefsTer27 frameshift_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.4161C>A p.Tyr1387Ter stop_gained Familial Maternal Extended multiplex 23933820 Lesca G , et al. (2013)
c.2041C>T p.Arg681Ter stop_gained Familial Maternal Extended multiplex 23933819 Lemke JR , et al. (2013)
c.1510C>T p.Arg504Trp missense_variant Unknown - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.1123-1G>T - splice_site_variant Familial Maternal Multi-generational 30544257 Strehlow V , et al. (2018)
c.2179G>A p.Ala727Thr missense_variant Familial Maternal Multiplex 38374498 Purvi Majethia et al. (2024)
c.2041C>T p.Arg681Ter stop_gained Familial Paternal Multi-generational 30544257 Strehlow V , et al. (2018)
c.236C>G p.Pro79Arg missense_variant Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.2146G>A p.Ala716Thr missense_variant Familial Maternal Multi-generational 23933820 Lesca G , et al. (2013)
c.2063G>C p.Gly688Ala missense_variant De novo - Possible multi-generational 28440294 Chen XS , et al. (2017)
c.1639_1641del p.Ser547del inframe_deletion Unknown Not maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.1585del p.Val529TrpfsTer22 frameshift_variant Familial Maternal Multiplex 23933819 Lemke JR , et al. (2013)
c.2334_2338del p.Leu779SerfsTer5 frameshift_variant Familial Paternal Simplex 23933819 Lemke JR , et al. (2013)
c.1007+1G>A p.Phe139IlefsTer15 splice_site_variant Familial Paternal Simplex 23933818 Carvill GL , et al. (2013)
c.90dup p.Pro31SerfsTer107 frameshift_variant Familial Maternal Multi-generational 23933819 Lemke JR , et al. (2013)
c.1586del p.Val529GlyfsTer22 frameshift_variant Unknown - Multi-generational 28109652 von Stlpnagel C , et al. (2017)
NM_001009184.2:c.445_448delGCGTins69 p.Ala149SerfsTer8 frameshift_variant Unknown - - 30544257 Strehlow V , et al. (2018)
c.1928C>A p.Ala643Asp missense_variant De novo (germline mosaicism) - Multiplex 29644724 Fernndez-Marmiesse A , et al. (2018)
c.1007+1G>A p.Phe139IlefsTer15 splice_site_variant Familial Maternal and paternal Multi-generational 23933818 Carvill GL , et al. (2013)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2169-7736A>G;c.2325-7736A>G;c.1698-7736A>G - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.2168+4735G>T;c.2324+4735G>T;c.1697+4735G>T A/C intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
c.2316-35G>C - intron_variant - - - 15830322 Barnby G , et al. (2005)
c.1576T>C p.(=) synonymous_variant - - - 15830322 Barnby G , et al. (2005)
c.*1212C>T;c.*1418C>T - 3_prime_UTR_variant - - - 15830322 Barnby G , et al. (2005)
SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

7/1/2020
1
icon
1

Score remained at 1

Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression2020] [Clustering by phenotype and genome-wide association study in autism2020] [An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020] [Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[Autism risk in offspring can be assessed through quantification of male sperm mosaicism.2019]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.2019]
1/1/2019
4
icon
3

Decreased from 4 to 3

Description

Genetic association was observed between the GRIN2A gene and autism in a cohort from the International Molecular Genetics Study of Autism Consortium (IMGSAC) in Barnby et al., 2005. Heterozygous variants in the GRIN2A gene are associated with focal epilepsy and speech disorder (FESD) with or without mental retardation (OMIM 245570), a childhood-onset seizure disorder with a highly variable phenotype. Strehlow et al., 2018 characterized a cohort of 248 individuals with pathogenic and likely pathogenic GRIN2A variants and found that in a subset of 70 cases with available information about neuropsychiatric co-morbidities, autism spectrum disorder was present in 6 cases.

Reports Added
[Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation.2014] [Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy.2017] [GRIN2A-related disorders: genotype and functional consequence predict phenotype.2018]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Functional Properties of Human NMDA Receptors Associated with Epilepsy-Related Mutations of GluN2A Subunit.2017] [Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.2017]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.2011] [Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.2005] [Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.2010] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [GRIN2A mutations cause epilepsy-aphasia spectrum disorders.2013] [Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.2013] [GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.2013] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.1988] [Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.1994] [Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons.2006] [Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses.2006] [Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors.2006] [NMDA receptor function: subunit composition versus spatial distribution.2006] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.2016] [Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.2017] [Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.2017] [A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.2017] [Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.2017] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Functional assessment of the NMDA receptor variant GluN2A R586K.2017] [Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology.2017] [Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.2017] [A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.2017] [Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.2016]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Reports Added
[Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.2011] [Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.2005] [Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.2010] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [GRIN2A mutations cause epilepsy-aphasia spectrum disorders.2013] [Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.2013] [GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.2013] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.1988] [Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.1994] [Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons.2006] [Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses.2006] [Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors.2006] [NMDA receptor function: subunit composition versus spatial distribution.2006] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

There is association and linkage evidence for the GRIN2A gene. For example, genetic association has been found between the GRIN2A gene and autism in an IMGSAC cohort (Barnby et al., 2005).

Krishnan Probability Score

Score 0.63703855943237

Ranking 56/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99804480805101

Ranking 1249/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94842664598765

Ranking 17679/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 9

Ranking 197/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.085195646077055

Ranking 11774/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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