ACVR2B

activin A receptor type 2B, the group of Type 2 receptor serine/threonine kinases

Basic information

Region (hg38): 3:38453889-38493142

Links

ENSG00000114739 ∙ NCBI:93 ∙ OMIM:602730 ∙ HGNC:174 ∙ Uniprot:Q13705 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• heterotaxy, visceral, 4, autosomal (Limited), mode of inheritance: AD
• heterotaxy, visceral, 4, autosomal (Strong), mode of inheritance: AD
• heterotaxy, visceral, 4, autosomal (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Heterotaxy, visceral, 4, autosomal	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Gastrointestinal; Musculoskeletal	9916847

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACVR2B gene.

• Heterotaxy, visceral, 4, autosomal (283 variants)
• not provided (27 variants)
• Visceral heterotaxy (26 variants)
• not specified (10 variants)
• Inborn genetic diseases (8 variants)
• ACVR2B-related condition (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACVR2B gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	21	6	32
missense		1	39	4		44
nonsense						0
start loss			1			1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			2	4	2	8
non coding			142	19	79	240
Total	0	1	189	44	85

Variants in ACVR2B

This is a list of pathogenic ClinVar variants found in the ACVR2B region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-38454302-C-T		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Apr 27, 2017)
3-38454323-A-G		Heterotaxy, visceral, 4, autosomal	Uncertain significance (May 01, 2018)
3-38454328-G-C			Likely benign (-)
3-38454331-G-A		Heterotaxy, visceral, 4, autosomal	Likely benign (Feb 21, 2022)
3-38454332-C-T		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Feb 04, 2022)
3-38454342-C-T		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Nov 19, 2021)
3-38454344-C-T		Heterotaxy, visceral, 4, autosomal • not specified	Uncertain significance (Jun 02, 2023)
3-38454346-C-A		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Jan 15, 2018)
3-38454367-G-A		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Jan 13, 2018)
3-38454382-C-T		Heterotaxy, visceral, 4, autosomal	Likely benign (May 03, 2021)
3-38454382-CTG-C		ACVR2B-related disorder	Likely benign (Nov 19, 2022)
3-38454574-C-T			Benign (Nov 10, 2018)
3-38477295-C-T		ACVR2B-related disorder	Uncertain significance (Sep 21, 2022)
3-38477296-G-A		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Aug 10, 2021)
3-38477333-C-T		Heterotaxy, visceral, 4, autosomal	Likely benign (Feb 15, 2023)
3-38477334-G-A		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Jun 13, 2022)
3-38477346-C-T		Heterotaxy, visceral, 4, autosomal	Likely benign (Dec 24, 2020)
3-38477353-G-A		Heterotaxy, visceral, 4, autosomal • not specified	Benign/Likely benign (Nov 22, 2023)
3-38477377-G-A		not specified	Uncertain significance (Mar 04, 2024)
3-38477377-G-T		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Nov 07, 2018)
3-38477381-C-T		Heterotaxy, visceral, 4, autosomal	Benign (Oct 29, 2023)
3-38477382-G-A		Heterotaxy, visceral, 4, autosomal	Uncertain significance (Aug 16, 2022)
3-38477411-C-T			Likely benign (Jan 02, 2019)
3-38477444-C-T		Heterotaxy, visceral, 4, autosomal • ACVR2B-related disorder	Likely benign (Aug 07, 2022)
3-38477477-C-T		Heterotaxy, visceral, 4, autosomal	Likely benign (Jul 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACVR2B	protein_coding	protein_coding	ENST00000352511	11	39292

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.834	0.166	125742	0	6	125748	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.04	196	295	0.665	0.0000205	3322
Missense in Polyphen		35	91.177	0.38387		1085
Synonymous	-1.51	147	125	1.17	0.00000918	1026
Loss of Function	4.02	5	27.9	0.179	0.00000149	305

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	0.0000462	0.0000462
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). The type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. {ECO:0000269|PubMed:8622651}.
• Disease: DISEASE: Heterotaxy, visceral, 4, autosomal (HTX4) [MIM:613751]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. HTX4 clinical features include dextrocardia, right aortic arch and a right-sided spleen, anomalies of the inferior and the superior vena cava, atrial ventricular canal defect with dextro-transposed great arteries, pulmonary stenosis, polysplenia and midline liver. {ECO:0000269|PubMed:9916847}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);TGF-Core;Mesodermal Commitment Pathway;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;Developmental Biology;Regulation of signaling by NODAL;Signal Transduction;Signaling by Activin;TGF-beta super family signaling pathway canonical;Signaling by NODAL;IL-7 signaling;BMP Signalling Pathway;JAK STAT pathway and regulation;EPO signaling;BMP2 signaling TGF-beta MV;VEGF;Signaling by BMP;Signaling by TGF-beta family members;ALK1 signaling events (Consensus)

Recessive Scores

• pRec: 0.315

Intolerance Scores

• loftool: 0.0145
• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.88

Haploinsufficiency Scores

• pHI: 0.859
• hipred: Y
• hipred_score: 0.853
• ghis: 0.457

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acvr2b
• Phenotype: growth/size/body region phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; immune system phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; renal/urinary system phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: acvr2ba
• Affected structure: endochondral bone
• Phenotype tag: abnormal
• Phenotype quality: aplastic

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;gastrulation with mouth forming second;kidney development;lymphangiogenesis;blood vessel remodeling;regulation of transcription, DNA-templated;protein phosphorylation;signal transduction;transmembrane receptor protein serine/threonine kinase signaling pathway;transforming growth factor beta receptor signaling pathway;determination of left/right symmetry;pattern specification process;mesoderm development;heart development;response to glucose;post-embryonic development;anterior/posterior pattern specification;insulin secretion;lung development;positive regulation of bone mineralization;BMP signaling pathway;pancreas development;activation of protein kinase activity;activin receptor signaling pathway;positive regulation of activin receptor signaling pathway;organ growth;odontogenesis of dentin-containing tooth;positive regulation of osteoblast differentiation;embryonic foregut morphogenesis;skeletal system morphogenesis;roof of mouth development;lymphatic endothelial cell differentiation;artery development;venous blood vessel development;retina vasculature development in camera-type eye;negative regulation of cold-induced thermogenesis
• Cellular component: cytoplasm;plasma membrane;integral component of plasma membrane;protein-containing complex;receptor complex;activin receptor complex
• Molecular function: protein serine/threonine kinase activity;protein serine/threonine/tyrosine kinase activity;transforming growth factor beta-activated receptor activity;transforming growth factor beta receptor activity, type II;protein binding;ATP binding;activin receptor activity, type II;growth factor binding;type I transforming growth factor beta receptor binding;SMAD binding;metal ion binding;activin binding