CAPS2

Genetic evidence – Published: PMID: 37644014 — One proband from a consanguineous family, homozygous for NM_032606.5:c.1490_1491del (predicted loss-of-function); AR inheritance; intellectual disability/neurodevelopmental disorder; no reported segregation; no case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0. PMID: 27431290 — One proband from a consanguineous family, homozygous for NM_032606.5:c.1490_1491del (predicted loss-of-function); AR inheritance; intellectual disability/neurodevelopmental disorder; no reported segregation; no case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0. Published genetic evidence total = 2.0 / 12 Genetic evidence – Our cases: Case 1 — One proband with homozygous NM_001286548.3:c.1148A>G; p.(Ter383Trpext*) (predicted loss-of-function); motor delay and dysmorphic features; positive consanguinity; similarly affected sibling reported but not genotyped; no segregation data; no case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0. Case 2 — One proband with homozygous NM_001286548.3:c.1148A>G; p.(Ter383Trpext*) (predicted loss-of-function); autism spectrum disorder, intellectual disability, severe speech delay, epilepsy in remission; positive consanguinity; affected sibling reported but not genotyped; no segregation data; no case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0. Our cases contribution = 2.0 / 12 Total genetic evidence (published + current) = 4.0 / 12 Experimental evidence – Published: PMIDs: 17380209, 19238500, 21173225 — Functional and animal model data demonstrating CADPS2 involvement in dense-core vesicle exocytosis and neurotrophin release, with knockout mouse models showing neurodevelopmental and behavioral abnormalities consistent with ASD/ID spectrum. Functional role in neuronal secretion = 1.0; animal model phenotypic overlap = 2.0. Experimental evidence total = 3.0 / 6 Overall score (with current cases) = 7.0

intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAPS2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 89

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001355024.4. 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			1 clinvar		2 clinvar	3
missense			80 clinvar	4 clinvar	1 clinvar	85
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	86	4	3	93

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001355024.4	RefSeq	NP_001341953.2	16	MANE Select
ENST00000699294.1	Ensembl	ENSP00000514274.1	16	MANE Select
NM_001286547.3	RefSeq	NP_001273476.1	15	Standard
NM_001286548.3	RefSeq	NP_001273477.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Molecular Function

calcium ion binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409445
Coding exons: 18
Length: 114950
Individuals with no LoFs: 125625
Homozygous LoFs: 0
Heterozygous LoFs: 110
Defined: 125735
p: 0.000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0866	271	267	1.01	0.0000127	3675
Missense (PolyPhen)		66	64.39	1.025		861
Synonymous	1.09	75	88.0	0.852	0.00000401	971
Loss of Function	0.0994	36	36.6	0.982	0.00000210	445

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00097	0.00093	rare
Ashkenazi Jewish	0.0018	0.0017	notable
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00033	0.00033	rare
South Asian	0.00037	0.00036	rare
Other	0.00067	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0922

Intolerance Scores

LoFtool: 0.570
RVIS EVS: 0.2
RVIS percentile EVS: 67.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.410

Gene Damage Prediction

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