Human Gene Module / Chromosome 12 / ATP2B1

ATP2B1ATPase plasma membrane Ca2+ transporting 1

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
1 / 2
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
12q21.33
Associated Disorders
-
Relevance to Autism

Rahimi et al., 2022 clinically described a cohort of 12 unrelated individuals with variants in the ATP2B1 gene and an overlapping phenotype of mild to moderate developmental delay/intellectual disability; five of these individuals were diagnosed with autism spectrum disorder. Additional functional characterization of the nine ATP2B1 missense variants identified in affected individuals in this report by Ca2+ imaging in transfected HEK293 cells showed that all variants led to a signficant decrease in Ca2+ export capacity compared to wild-type, demonstrating their pathogencity.

Molecular Function

The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 1.

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Reports related to ATP2B1 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary - Rahimi MJ et al. (2022) No ASD, ID, epilepsy/seizures
2 Support - Zhou X et al. (2022) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.458G>A p.Trp153Ter stop_gained Unknown - - 35358416 Rahimi MJ et al. (2022)
c.487G>A p.Val163Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2632C>T p.Gln878Ter stop_gained De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.1789C>T p.Arg597Ter stop_gained Unknown - Unknown 35358416 Rahimi MJ et al. (2022)
c.716A>G p.Asp239Gly missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.791C>T p.Thr264Ile missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.1274C>A p.Thr425Lys missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.1376A>G p.His459Arg missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.2288G>C p.Arg763Pro missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.2365C>T p.Arg789Cys missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.2470G>A p.Glu824Lys missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.2570A>G p.Gln857Arg missense_variant De novo - Simplex 35358416 Rahimi MJ et al. (2022)
c.2972G>A p.Arg991Gln missense_variant Unknown Not maternal - 35358416 Rahimi MJ et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

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
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.61548960442029

Ranking 115/25841 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 0.99999754218807

Ranking 357/18225 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 0.94148223344687

Ranking 14949/18665 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 0.41486722880183

Ranking 1287/20870 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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