CACNA1ACalcium channel, voltage-dependent, P/Q type, alpha 1A subunit

SFARI Gene Score

High Confidence, Syndromic Criteria 1.1, Syndromic

Autism Reports / Total Reports

14 / 45

Rare Variants / Common Variants

122 / 2

Aliases

CACNA1A, APCA, BI, CACNL1A4, CAV2.1, EA2, FHM, HPCA, MHP, MHP1, SCA6

Associated Syndromes

Chromosome Band

19p13.13

Associated Disorders

DD/NDD, ID, EP, EPS, ASD

Relevance to Autism

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013). Lipman et al., 2022 reported 47 individuals with 33 unique pathogenic or likely pathogenic variants in CACNA1A; developmental delay/intellectual disability was observed in 96% of affected individuals, and autism spectrum disorder was reported in 23% of affected individuals.

Molecular Function

This gene encodes the pore-forming alpha-1A subunit, which is predominantly expressed in neuronal tissue, for voltage-dependent calcium channels. Mutations in this gene are associated with several neurological disorders: episodic ataxia, type 2 (OMIM 108500); migraine, familial hemiplegic, 1 (OMIM 141500); and spinocerebellar atxia 6 (OMIM 183086).

External Links

Gene Card Open Targets Platform gnomAD browser SynGO portal PubMed

Human

Entrez Gene OMIM UniProt HumanBase VariCarta

SFARI Genomic Platforms

GPF browser SFARI genome browser

Reports (45)
Variants (124)
Gene Score

Reports related to CACNA1A (45 Reports)

#	Type	Title	Author, Year	Autism Report	Associated Disorders
1	Support	CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures	Rossignol E , et al. (2013)	No	-
2	Support	The contribution of de novo coding mutations to autism spectrum disorder	Iossifov I et al. (2014)	Yes	-
3	Primary	CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms	Damaj L , et al. (2015)	Yes	Learning difficulties, ataxia
4	Negative Association	Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population	Li J , et al. (2015)	Yes	-
5	Recent Recommendation	Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy	Bomben VC , et al. (2016)	No	-
6	Recent Recommendation	De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia	Takata A , et al. (2016)	No	-
7	Support	De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)	No	-
8	Support	Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability	Lelieveld SH et al. (2016)	No	-
9	Support	Lessons learned from additional research analyses of unsolved clinical exome cases	Eldomery MK , et al. (2017)	No	Hypotonia, cerebellar atrophy
10	Support	A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology	Vissers LE , et al. (2017)	No	Oculomotor apraxia
11	Support	High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies	Hamdan FF , et al. (2017)	No	DD/ID
12	Support	Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant	Angelini C , et al. (2018)	No	ID, ataxia
13	Support	The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders	Jiao Q , et al. (2019)	No	ID
14	Support	Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes	Xiong J , et al. (2019)	Yes	Epilepsy/seizures
15	Support	Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants	Lecoquierre F , et al. (2019)	No	-
16	Support	The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children	Long S , et al. (2019)	Yes	-
17	Support	The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing	Wang J et al. (2020)	No	-
18	Support	-	Rodin RE et al. (2021)	Yes	-
19	Support	-	Mojarad BA et al. (2021)	No	ID
20	Support	-	Liu L et al. (2021)	No	ASD
21	Support	-	Valentino F et al. (2021)	No	DD, stereotypy
22	Support	-	Chen S et al. (2021)	Yes	Epilepsy/seizures
23	Support	-	Viggiano M et al. (2022)	Yes	-
24	Support	-	Tex.) (2022)	No	-
25	Support	-	Chuan Z et al. (2022)	No	DD
26	Support	-	Li XL et al. (2022)	No	ID
27	Support	-	Teles E Silva AL et al. (2022)	Yes	-
28	Recent Recommendation	-	Lipman AR et al. (2022)	No	ASD, ADHD, OCD, epilepsy/seizures
29	Support	-	Zhou X et al. (2022)	Yes	-
30	Support	-	Chen WX et al. (2022)	Yes	-
31	Support	-	Kramer AA et al. (2023)	No	Epilepsy/seizures, stereotypy
32	Recent Recommendation	-	Chen CY et al. (2023)	No	-
33	Support	-	Sanchis-Juan A et al. (2023)	No	DD, ID
34	Support	-	Sheth F et al. (2023)	Yes	DD, ID, epilepsy/seizures
35	Support	-	Kessi M et al. (2023)	No	ASD, epilepsy/seizures
36	Support	-	Ko YJ et al. (2023)	No	-
37	Support	-	Ana Karen Sandoval-Talamantes et al. (2023)	Yes	ID
38	Support	-	Luigi Vetri et al. (2024)	No	-
39	Support	-	Omri Bar et al. (2024)	Yes	ID
40	Support	-	Marketa Wayhelova et al. (2024)	No	-
41	Support	-	Magdalena Badura-Stronka et al. (2024)	No	ADHD
42	Support	-	Purvi Majethia et al. (2024)	No	DD
43	Support	-	Tamam Khalaf et al. (2024)	No	-
44	Support	-	Shenglan Li et al. (2024)	No	-
45	Support	-	Axel Schmidt et al. (2024)	No	Cognitive impairment, epilepsy/seizures

Rare Variants (122)

Allele Change	Residue Change	Variant Type	Inheritance Pattern	Parental Transmission	Family Type	PubMed ID	Author, Year
-	-	copy_number_loss	De novo	-	-	34800434	Chen S et al. (2021)
-	-	copy_number_loss	De novo	-	-	31031587	Xiong J , et al. (2019)
-	-	copy_number_loss	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.1635C>A	p.Tyr545Ter	stop_gained	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.2311A>T	p.Lys771Ter	stop_gained	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.4755+1G>T	-	splice_site_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.2134G>A	p.Ala712Thr	missense_variant	De novo	-	-	35982159	Zhou X et al. (2022)
c.118G>T	p.Gly40Trp	missense_variant	De novo	-	-	33432195	Rodin RE et al. (2021)
c.4991G>A	p.Arg1664Gln	missense_variant	De novo	-	-	32429945	Wang J et al. (2020)
c.5123T>C	p.Phe1708Ser	missense_variant	De novo	-	-	35982159	Zhou X et al. (2022)
c.5234T>A	p.Leu1745His	missense_variant	De novo	-	-	35982159	Zhou X et al. (2022)
c.4046G>A	p.Arg1349Gln	missense_variant	De novo	-	-	31139143	Long S , et al. (2019)
c.4177G>A	p.Val1393Met	missense_variant	De novo	-	-	35571021	Chuan Z et al. (2022)
c.5044T>C	p.Trp1682Arg	missense_variant	Unknown	-	-	35571021	Chuan Z et al. (2022)
c.3089+1G>A	p.?	splice_site_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.7302C>G	p.Tyr2434Ter	stop_gained	De novo	-	Simplex	35982159	Zhou X et al. (2022)
c.1843A>C	p.Ser615Arg	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.2134G>A	p.Ala712Thr	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.2137G>A	p.Val713Met	missense_variant	De novo	-	-	35722745	Lipman AR et al. (2022)
c.203G>T	p.Arg68Leu	missense_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.4043G>A	p.Arg1348Gln	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.4064C>A	p.Thr1355Asn	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.4064C>T	p.Thr1355Ile	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.4174G>A	p.Val1392Met	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.5422G>A	p.Val1808Ile	missense_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.203G>A	p.Arg68Gln	missense_variant	Unknown	-	-	38438125	Tamam Khalaf et al. (2024)
c.6553A>G	p.Thr2185Ala	missense_variant	Unknown	-	-	35350424	Viggiano M et al. (2022)
c.2140G>A	p.Val714Met	missense_variant	De novo	-	-	38256219	Luigi Vetri et al. (2024)
c.2143G>A	p.Asp715Asn	missense_variant	De novo	-	Simplex	37645600	Ko YJ et al. (2023)
c.6340-1G>Ap.?	p.?	splice_site_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.4106T>G	p.Val1369Gly	missense_variant	De novo	-	-	28333917	Vissers LE , et al. (2017)
c.4055G>A	p.Arg1352Gln	missense_variant	De novo	-	-	34356170	Valentino F et al. (2021)
c.5015G>C	p.Arg1672Pro	missense_variant	De novo	-	-	38593811	Shenglan Li et al. (2024)
c.1339G>T	p.Ala447Ser	missense_variant	Unknown	-	-	39039281	Axel Schmidt et al. (2024)
c.1748G>A	p.Arg583Gln	missense_variant	Unknown	-	-	39039281	Axel Schmidt et al. (2024)
c.7205C>A	p.Pro2402Gln	missense_variant	De novo	-	Simplex	33951346	Liu L et al. (2021)
c.3965G>A	p.Gly1322Glu	missense_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.5032C>T	p.Arg1678Cys	missense_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.5393C>T	p.Ser1798Leu	missense_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.4031C>A	p.Thr1344Lys	missense_variant	De novo	-	Simplex	37645600	Ko YJ et al. (2023)
c.4082_4084del	p.Lys1361del	inframe_deletion	De novo	-	-	31139143	Long S , et al. (2019)
c.4076C>A	p.Thr1359Asn	missense_variant	De novo	-	-	39039281	Axel Schmidt et al. (2024)
c.6881G>C	p.Arg2294Pro	missense_variant	De novo	-	Simplex	35982159	Zhou X et al. (2022)
c.2101G>A	p.Gly701Arg	missense_variant	De novo	-	Simplex	37555011	Kessi M et al. (2023)
C>T	p.Glu1979Lys	missense_variant	Familial	Maternal	-	35350424	Viggiano M et al. (2022)
c.4991G>A	p.Arg1664Gln	missense_variant	De novo	-	Simplex	37555011	Kessi M et al. (2023)
c.3798C>T	p.Ala1266=	synonymous_variant	De novo	-	Simplex	36320054	Chen WX et al. (2022)
-	-	copy_number_loss	Familial	Maternal	Multi-generational	25735478	Damaj L , et al. (2015)
c.652T>C	p.Ser218Pro	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.5263G>A	p.Glu1755Lys	missense_variant	De novo	-	-	31036916	Lecoquierre F , et al. (2019)
c.4043G>A	p.Arg1348Gln	missense_variant	De novo	-	-	38374498	Purvi Majethia et al. (2024)
c.4043G>A	p.Arg1348Gln	missense_variant	Unknown	-	-	38374498	Purvi Majethia et al. (2024)
c.185A>G	p.Tyr62Cys	missense_variant	De novo	-	Not simplex	37555011	Kessi M et al. (2023)
c.1360G>A	p.Ala454Thr	missense_variant	Familial	-	Simplex	38256266	Omri Bar et al. (2024)
c.1850T>C	p.Leu617Ser	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.2099G>A	p.Gly700Glu	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.2133C>G	p.Ile711Met	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.2134G>A	p.Ala712Thr	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.835C>T	p.Arg279Cys	missense_variant	Familial	Maternal	-	35722745	Lipman AR et al. (2022)
c.841del	p.Cys281AlafsTer29	frameshift_variant	Unknown	-	-	35722745	Lipman AR et al. (2022)
c.3948C>A	p.Asp1316Glu	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4028C>A	p.Ser1343Tyr	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4031T>C	p.Leu1344Pro	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4043G>A	p.Arg1348Gln	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4052G>A	p.Arg1351Gln	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4055C>T	p.Pro1352Leu	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4174G>A	p.Val1392Met	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4519G>A	p.Ala1507Thr	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4897G>A	p.Asp1633Asn	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4927G>A	p.Asp1643Asn	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.4997G>C	p.Arg1666Pro	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.5015G>C	p.Arg1672Pro	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.5120T>C	p.Ile1707Thr	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.5393C>T	p.Ser1798Leu	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.5417T>C	p.Val1806Ala	missense_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.2134G>A	p.Ala712Thr	missense_variant	De novo	-	Simplex	29100083	Hamdan FF , et al. (2017)
c.1173G>C	p.Gly391=	synonymous_variant	De novo	-	Simplex	25363768	Iossifov I et al. (2014)
c.1745G>A	p.Arg582Gln	missense_variant	Familial	Paternal	-	35722745	Lipman AR et al. (2022)
c.4174G>A	p.Val1392Met	missense_variant	De novo	-	Simplex	29100083	Hamdan FF , et al. (2017)
c.4500_4502del	p.Phe1501del	inframe_deletion	De novo	-	-	39039281	Axel Schmidt et al. (2024)
c.4930G>A	p.Asp1644Asn	missense_variant	De novo	-	Not simplex	37555011	Kessi M et al. (2023)
c.4174G>A	p.Val1392Met	missense_variant	Familial	Paternal	-	35722745	Lipman AR et al. (2022)
c.5018dup	p.Ile1674HisfsTer48	frameshift_variant	De novo	-	-	36938367	Kramer AA et al. (2023)
c.2668del	p.Ser890AlafsTer6	frameshift_variant	De novo	-	-	38256219	Luigi Vetri et al. (2024)
c.5900G>A	p.Arg1967Gln	missense_variant	Familial	Maternal	-	35350424	Viggiano M et al. (2022)
c.5015G>C	p.Arg1672Pro	missense_variant	De novo	-	Simplex	28327206	Eldomery MK , et al. (2017)
c.1100G>C	p.Arg367Thr	missense_variant	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.2124C>A	p.Phe708Leu	missense_variant	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.3233C>T	p.Ala1078Val	missense_variant	Familial	Paternal	Simplex	35600082	Li XL et al. (2022)
c.4891A>G	p.Ile1631Val	missense_variant	Familial	Maternal	Simplex	35600082	Li XL et al. (2022)
c.5978C>T	p.Pro1993Leu	missense_variant	Familial	Paternal	Simplex	35600082	Li XL et al. (2022)
c.6061G>A	p.Gly2021Arg	missense_variant	Familial	Maternal	Simplex	35600082	Li XL et al. (2022)
c.835C>T	p.Arg279Cys	missense_variant	Familial	Paternal	Simplex	37555011	Kessi M et al. (2023)
c.4174G>A	p.Val1392Met	missense_variant	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.5405T>G	p.Leu1802Arg	missense_variant	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.5335C>T	p.Arg1779Ter	stop_gained	Familial	Paternal	Multiplex	35722745	Lipman AR et al. (2022)
c.6901C>G	p.Pro2301Ala	missense_variant	Familial	Maternal	Simplex	37543562	Sheth F et al. (2023)
c.6772C>A	p.His2258Asn	missense_variant	De novo	-	Simplex	35668055	Teles E Silva AL et al. (2022)
c.3128A>G	p.Asn1043Ser	missense_variant	Unknown	-	Extended multiplex	37543562	Sheth F et al. (2023)
c.5014dup	p.Arg1672ProfsTer44	frameshift_variant	De novo	-	Simplex	35722745	Lipman AR et al. (2022)
c.2963_2964insG	p.Gly989ArgfsTer78	frameshift_variant	De novo	-	Simplex	35600082	Li XL et al. (2022)
c.2040_2041del	p.Gln681GlyfsTer103	frameshift_variant	De novo	-	-	27479843	Lelieveld SH et al. (2016)
c.115G>A	p.Gly39Ser	missense_variant	Unknown	-	-	38003033	Ana Karen Sandoval-Talamantes et al. (2023)
NM_023035.3:c.7178G>A	p.Gly2393Glu	missense_variant	Familial	Maternal	-	30945278	Jiao Q , et al. (2019)
c.835C>T	p.Arg279Cys	missense_variant	Familial	-	Multi-generational	30142438	Angelini C , et al. (2018)
c.2024_2038del	p.Tyr675_Lys679del	inframe_deletion	Familial	Maternal	-	35722745	Lipman AR et al. (2022)
c.4880G>A	p.Arg1627His	missense_variant	Unknown	-	-	38003033	Ana Karen Sandoval-Talamantes et al. (2023)
c.6494G>A	p.Arg2165His	missense_variant	Unknown	-	-	38003033	Ana Karen Sandoval-Talamantes et al. (2023)
c.3832C>T	p.Arg1278Ter	stop_gained	Familial	Paternal	Multi-generational	25735478	Damaj L , et al. (2015)
c.2042_2043del	p.Gln681ArgfsTer103	frameshift_variant	Unknown	-	Simplex	33526774	Mojarad BA et al. (2021)
c.4265del	p.Gly1422AlafsTer11	frameshift_variant	Familial	Maternal	Simplex	37555011	Kessi M et al. (2023)
c.3411dup	p.Lys1138GlnfsTer6	frameshift_variant	Familial	Paternal	-	38321498	Marketa Wayhelova et al. (2024)
c.2040_2041del	p.Gln681GlyfsTer103	frameshift_variant	Unknown	-	Simplex	37541188	Sanchis-Juan A et al. (2023)
c.873G>A	p.Trp291Ter	splice_site_variant	Familial	Maternal	Multi-generational	25735478	Damaj L , et al. (2015)
c.5419G>A	p.Ala1807Thr	missense_variant	Familial	Maternal	Multiplex	38328757	Magdalena Badura-Stronka et al. (2024)
c.2867_2869del	p.Asp956del	frameshift_variant	Familial	Maternal and paternal	Multi-generational	25735478	Damaj L , et al. (2015)
c.301G>C	p.Glu101Gln	missense_variant	De novo	-	-	27476654	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.653C>T	p.Ser218Leu	missense_variant	Unknown	-	-	27476654	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.2137G>A	p.Ala713Thr	missense_variant	De novo	-	-	27476654	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.4531G>T	p.Ala1511Ser	missense_variant	De novo	-	-	27476654	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.2137G>A	p.Ala713Thr	missense_variant	Familial	Maternal	Multiplex	27476654	Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
ENSG00000141837:ENST00000573710:exon19:c.A2504C:p.N835T,ENSG00000141837:ENST00000360228:exon19:c.A25	-	missense_variant	De novo	-	-	33432195	Rodin RE et al. (2021)

Common Variants (2)

Status	Allele Change	Residue Change	Variant Type	Inheritance Pattern	Paternal Transmission	Family Type	PubMed ID	Author, Year
	c.293+17663A>C	-	intron_variant	-	-	-	26566276	Li J , et al. (2015)
	c.294-22490A>G	-	intron_variant	-	-	-	26566276	Li J , et al. (2015)

Current Score
Scoring History
3rd Party Scoring

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

See SFARI Gene'scoring criteria

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.

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022

Increased from S to 1S

Description

4/1/2021

Increased from S to S

Description

Reports Added

[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021]

1/1/2021

Increased from S to S

Description

Reports Added

[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021] [Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia2021]

4/1/2020

Increased from S to S

Description

Reports Added

[The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing2020]

10/1/2019

Increased from S to S

New Scoring Scheme

Description

Reports Added

[New Scoring Scheme]

7/1/2019

Increased from S to S

Description

Reports Added

[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019]

4/1/2019

Increased from S to S

Description

Reports Added

[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019] [Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]

10/1/2018

Increased from S to S

Description

Reports Added

[Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.2018]

Krishnan Probability Score

Score 0.61038153156471

Ranking 231/25841 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 0.99999999977629

Ranking 80/18225 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 0.94806684873626

Ranking 17532/18665 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

Zhang D Score

Score 0.41840424797678

Ranking 1256/20870 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

Human Gene Module / Chromosome 19 / CACNA1A

CACNA1ACalcium channel, voltage-dependent, P/Q type, alpha 1A subunit

SFARI Gene Score

Autism Reports / Total Reports

Rare Variants / Common Variants

Aliases

Associated Syndromes

Chromosome Band

Associated Disorders

Relevance to Autism

Molecular Function

External Links

Human

SFARI Genomic Platforms

Reports related to CACNA1A (45 Reports)

Rare Variants (122)

Common Variants (2)

SFARI Gene score

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met

High Confidence

Syndromic

4/1/2022

Increased from S to 1S

Description

4/1/2021

Increased from S to S

Description

Reports Added

1/1/2021

Increased from S to S

Description

Reports Added

4/1/2020

Increased from S to S

Description

Reports Added

10/1/2019

Increased from S to S

New Scoring Scheme

Description

Reports Added

7/1/2019

Increased from S to S

Description

Reports Added

4/1/2019

Increased from S to S

Description

Reports Added

10/1/2018

Increased from S to S

Description

Reports Added

Krishnan Probability Score

Score 0.61038153156471

Ranking 231/25841 scored genes

ExAC Score

Score 0.99999999977629

Ranking 80/18225 scored genes

Sanders TADA Score

Score 0.94806684873626

Ranking 17532/18665 scored genes

Zhang D Score

Score 0.41840424797678

Ranking 1256/20870 scored genes