DGCR6

Summary

DGCR6 (DiGeorge syndrome critical region gene 6, HGNC:2846) is a protein-coding gene on chromosome 22q11.21, encoding Protein DGCR6 (Q14129). May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.

DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia.

Source: NCBI Gene 8214 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 79 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 39
• MANE Select transcript: NM_005675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2846
Approved symbol	DGCR6
Name	DiGeorge syndrome critical region gene 6
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183628
Ensembl biotype	protein_coding
OMIM	601279
Entrez	8214

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000331444, ENST00000413981, ENST00000427407, ENST00000436645, ENST00000477156, ENST00000480608, ENST00000483718, ENST00000608842, ENST00000881231, ENST00000932120

RefSeq mRNA: 1 — MANE Select: NM_005675 NM_005675

CCDS: CCDS13753

Canonical transcript exons

ENST00000331444 — 5 exons

Exon	Start	End
ENSE00001705371	18911540	18912088
ENSE00001782347	18906320	18906484
ENSE00003530026	18906565	18906725
ENSE00003687876	18910888	18911028
ENSE00003690027	18910172	18910272

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 94.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9049 / max 271.1863, expressed in 1517 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191024	6.9049	1517

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue	UBERON:0001134	94.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.07	gold quality
gastrocnemius	UBERON:0001388	93.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.50	gold quality
cerebellar hemisphere	UBERON:0002245	93.09	gold quality
cerebellar cortex	UBERON:0002129	93.02	gold quality
cerebellum	UBERON:0002037	93.01	gold quality
muscle of leg	UBERON:0001383	92.42	gold quality
right frontal lobe	UBERON:0002810	92.12	gold quality
hypothalamus	UBERON:0001898	91.70	gold quality
anterior cingulate cortex	UBERON:0009835	91.68	gold quality
amygdala	UBERON:0001876	91.56	gold quality
temporal lobe	UBERON:0001871	91.52	gold quality
Ammon’s horn	UBERON:0001954	91.23	gold quality
nucleus accumbens	UBERON:0001882	91.12	gold quality
substantia nigra	UBERON:0002038	90.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.63	gold quality
putamen	UBERON:0001874	90.51	gold quality
brain	UBERON:0000955	90.25	gold quality
primary visual cortex	UBERON:0002436	90.09	gold quality
cerebral cortex	UBERON:0000956	89.96	gold quality
caudate nucleus	UBERON:0001873	89.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.39	gold quality
frontal cortex	UBERON:0001870	89.04	gold quality
superior frontal gyrus	UBERON:0002661	88.52	gold quality
apex of heart	UBERON:0002098	87.93	gold quality
pituitary gland	UBERON:0000007	87.30	gold quality
heart left ventricle	UBERON:0002084	87.27	gold quality
muscle tissue	UBERON:0002385	87.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.07	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.89
E-MTAB-6142	no	36.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting DGCR6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-3974	96.56	66.22	928
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982

Literature-anchored findings (GeneRIF, showing 5)

• Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia (PMID:11891283)
• A compelling genetic hypothesis for a complex disease: PRODH2/DGCR6 variation leads to schizophrenia susceptibility. (PMID:11959925)
• GABAB1 subunits interact with DGCR6 in the endoplasmic reticulum prior to their recruitment into functional GABAB receptors. (PMID:20036641)
• Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects. (PMID:22832905)
• the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, was studied. (PMID:26978485)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dgcr6	ENSDARG00000005500
mus_musculus	Dgcr6	ENSMUSG00000003531
rattus_norvegicus	Dgcr6	ENSRNOG00000001880
drosophila_melanogaster	gdl	FBGN0001099

Paralogs (2): DGCR6L (ENSG00000128185), (ENSG00000278817)

Protein

Protein identifiers

Protein DGCR6 — Q14129 (reviewed: Q14129)

Alternative names: DiGeorge syndrome critical region 6

All UniProt accessions (5): Q14129, K7ELY4, K7EPQ2, Q6FGH4, X5D7D2

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in neural crest cell migration into the third and fourth pharyngeal pouches.

Subcellular location. Nucleus.

Tissue specificity. Found in all tissues examined with highest expression in liver, heart and skeletal muscle. Lower levels in pancreas and placenta. Weak expression in brain.

Induction. Increased levels in several tumor cell lines, including lung and colon adenocarcinomas and mammary carcinomas. Strongly induced in Burkitt’s lymphoma and lymphocytes transformed by EBV.

Similarity. Belongs to the gonadal family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14129-1	1	yes
Q14129-2	2, C

RefSeq proteins (1): NP_005666* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010849	Gonadal	Family

Pfam: PF07324

UniProt features (6 total): splice variant 2, chain 1, coiled-coil region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14129-F1	86.83	0.72

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 181 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, TERAMOTO_OPN_TARGETS_CLUSTER_4, GCM_PRKCG, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GCM_RING1, BLALOCK_ALZHEIMERS_DISEASE_UP, GCM_FCGR2B, GCM_DPF2, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, GCM_TEC

GO Biological Process (2): cell adhesion (GO:0007155), animal organ morphogenesis (GO:0009887)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
anatomical structure morphogenesis	1
animal organ development	1
binding	1
intracellular membrane-bounded organelle	1
external encapsulating structure	1

Protein interactions and networks

STRING

470 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DGCR6	PRODH	O43272	890
DGCR6	DGCR2	P98153	842
DGCR6	ZNF74	Q16587	842
DGCR6	PRODH	O43272	796
DGCR6	HIRA	P54198	762
DGCR6	TBX1	O43435	705
DGCR6	SERPIND1	P05546	679
DGCR6	GNB1L	Q9BYB4	647
DGCR6	COMT	P21964	635
DGCR6	ZDHHC8	Q9ULC8	597
DGCR6	UFD1	Q92890	570
DGCR6	GSC2	O15499	557
DGCR6	MRPL40	Q9NQ50	512
DGCR6	PRODH2	Q9UF12	476
DGCR6	TMEM191B	P0C7N4	476

IntAct

36 interactions, top by confidence:

A	B	Type	Score
KRTAP12-2	DGCR6	psi-mi:“MI:0915”(physical association)	0.560
DGCR6	AKAP8L	psi-mi:“MI:0915”(physical association)	0.560
FH	DGCR6	psi-mi:“MI:0915”(physical association)	0.560
DGCR6	INIP	psi-mi:“MI:0915”(physical association)	0.560
DGCR6	ESS2	psi-mi:“MI:0915”(physical association)	0.560
BMP2K	DGCR6	psi-mi:“MI:0915”(physical association)	0.490
DGCR6	REXO1	psi-mi:“MI:0915”(physical association)	0.400
DGCR6	ARNT2	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	C3orf62	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	CTBP1	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	DLGAP2	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	DLX2	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	EFEMP2	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	KLHL12	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	NQO2	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	NUP54	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	NUP62	psi-mi:“MI:0915”(physical association)	0.370
DGCR6	PRDM14	psi-mi:“MI:0915”(physical association)	0.370
NPAP1	ACACB	psi-mi:“MI:0914”(association)	0.350
XKR4	CCNC	psi-mi:“MI:0914”(association)	0.350
TBC1D4	DNAJC13	psi-mi:“MI:0914”(association)	0.350
DGCR6	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.000
DGCR6	INIP	psi-mi:“MI:0915”(physical association)	0.000
DGCR6	AKAP8L	psi-mi:“MI:0915”(physical association)	0.000
DGCR6	FH	psi-mi:“MI:0915”(physical association)	0.000
DGCR6	ESS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (75): DGCR6 (Two-hybrid), DGCR6 (Two-hybrid), DGCR6 (Two-hybrid), DGCR6 (Two-hybrid), KRTAP12-2 (Two-hybrid), DGCR6 (Affinity Capture-MS), REXO1 (Affinity Capture-MS), DGCR6 (Affinity Capture-MS), DGCR6 (Affinity Capture-MS), DGCR6 (Affinity Capture-MS), DGCR6 (Two-hybrid), DGCR6 (Proximity Label-MS), DGCR6 (Proximity Label-MS), DGCR6 (Proximity Label-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A5D8V7, A5PK16, A6QP29, A7E3N7, A8K8P3, A9CB34, B0KWR6, B5DFA1, D3ZI76, G3HQ82, O73770, P0C7M6, P41002, Q14129, Q14DK4, Q15051, Q3SYS7, Q3UK37, Q3UZY0, Q5SNV9, Q5SXM2, Q60953, Q60I26, Q60I27, Q69ZT1, Q6NUI2, Q8BP00, Q8BP86, Q8C1F5, Q8C2K1, Q8CJ00, Q8IV45, Q8NCU4, Q8NE28, Q8NEE8, Q8TE82, Q95KD7

Diamond homologs: O35347, O73770, P22468, Q14129, Q9BY27

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

79 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	56
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1072697	NC_000022.10:g.(?18899287)(18925066_?)del	Pathogenic
1330197	GRCh37/hg19 22q11.21(chr22:18660135-21737597)x1	Pathogenic
2653434	GRCh37/hg19 22q11.21(chr22:18893888-18923800)x1	Pathogenic
3242286	GRCh37/hg19 22q11.21(chr22:18879656-19012096)x0	Pathogenic
394225	GRCh37/hg19 22q11.21(chr22:18650664-21440455)x1	Pathogenic
59280	GRCh38/hg38 22q11.21(chr22:18050488-18955291)x3	Pathogenic
809397	GRCh37/hg19 22q11.21(chr22:18893887-18923800)x1	Likely pathogenic

SpliceAI

1149 predictions. Top by Δscore:

Variant	Effect	Δscore
22:18906474:G:GT	donor_gain	1.0000
22:18906486:T:A	donor_loss	1.0000
22:18906563:A:AG	acceptor_gain	1.0000
22:18906564:G:GG	acceptor_gain	1.0000
22:18906564:GCTCA:G	acceptor_gain	1.0000
22:18910168:CCA:C	acceptor_loss	1.0000
22:18910169:CA:C	acceptor_loss	1.0000
22:18910170:A:AG	acceptor_gain	1.0000
22:18910171:G:GA	acceptor_gain	1.0000
22:18910171:GT:G	acceptor_gain	1.0000
22:18910865:C:CA	acceptor_gain	1.0000
22:18910868:C:CA	acceptor_gain	1.0000
22:18910874:C:A	acceptor_gain	1.0000
22:18910881:AC:A	acceptor_gain	1.0000
22:18910882:C:CA	acceptor_gain	1.0000
22:18910883:G:A	acceptor_gain	1.0000
22:18910884:GCAGG:G	acceptor_loss	1.0000
22:18910886:A:AG	acceptor_gain	1.0000
22:18910886:AGGC:A	acceptor_gain	1.0000
22:18910887:G:GG	acceptor_gain	1.0000
22:18910887:GGC:G	acceptor_gain	1.0000
22:18910887:GGCG:G	acceptor_gain	1.0000
22:18911027:AGGTC:A	donor_loss	1.0000
22:18911029:G:GA	donor_loss	1.0000
22:18911029:G:GG	donor_gain	1.0000
22:18913358:CTGGC:C	acceptor_gain	1.0000
22:18913359:TGGC:T	acceptor_gain	1.0000
22:18913363:C:CC	acceptor_gain	1.0000
22:18906473:G:GT	donor_gain	0.9900
22:18906485:G:GG	donor_gain	0.9900

AlphaMissense

1404 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:18910974:G:C	Q153H	0.996
22:18910974:G:T	Q153H	0.996
22:18906654:T:C	L67P	0.995
22:18906672:T:C	L73P	0.995
22:18911005:T:C	F164L	0.995
22:18911007:C:A	F164L	0.995
22:18911007:C:G	F164L	0.995
22:18906609:C:A	A52D	0.994
22:18906606:T:C	L51P	0.993
22:18906642:T:G	I63S	0.993
22:18910949:T:C	L145P	0.993
22:18911006:T:C	F164S	0.993
22:18910982:T:C	L156P	0.992
22:18906667:G:C	Q71H	0.991
22:18906667:G:T	Q71H	0.991
22:18906679:A:C	E75D	0.991
22:18906679:A:T	E75D	0.991
22:18910971:G:C	Q152H	0.991
22:18910971:G:T	Q152H	0.991
22:18911562:T:C	L179P	0.990
22:18911571:T:C	L182P	0.990
22:18906457:T:C	L28S	0.989
22:18906642:T:A	I63N	0.989
22:18906642:T:C	I63T	0.989
22:18906687:T:C	L78P	0.989
22:18906699:G:C	R82P	0.989
22:18906618:T:A	L55H	0.988
22:18906618:T:C	L55P	0.988
22:18910982:T:A	L156Q	0.988
22:18911015:C:T	T167I	0.988

dbSNP variants (sampled 300 via entrez): RS1001061843 (22:18904245 G>A), RS1001172360 (22:18909211 C>G,T), RS1001539969 (22:18909400 G>A), RS1002139544 (22:18910355 G>A), RS1003549648 (22:18911189 G>A), RS1004132470 (22:18907627 T>A,G), RS1005133671 (22:18908752 AT>A), RS1005921633 (22:18904763 C>CG), RS1006021392 (22:18909952 A>G), RS1006926771 (22:18906242 G>A), RS1007546152 (22:18910633 G>T), RS1007880828 (22:18907537 A>C,T), RS1007944523 (22:18907007 C>A,G,T), RS1008936137 (22:18908517 C>A,T), RS1008947553 (22:18908281 C>T)

Disease associations

OMIM: gene MIM:601279 | disease phenotypes: MIM:239500, MIM:611867, MIM:600850, MIM:109730

GenCC curated gene-disease

Mondo (4): hyperprolinemia type 1 (MONDO:0009400), chromosome 22q11.2 deletion syndrome, distal (MONDO:0012740), schizophrenia 4 (MONDO:0010943), aortic valve disease 1 (MONDO:0024523)

Orphanet (2): Hyperprolinemia type 1 (Orphanet:419), Distal 22q11.2 microdeletion syndrome (Orphanet:261330)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000194	Open mouth
HP:0000201	Pierre-Robin sequence
HP:0000220	Velopharyngeal insufficiency
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000414	Bulbous nose
HP:0000430	Underdeveloped nasal alae
HP:0000581	Blepharophimosis
HP:0000598	Abnormality of the ear
HP:0000627	Posterior embryotoxon
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000829	Hypoparathyroidism
HP:0001155	Abnormality of the hand
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001328	Specific learning disability
HP:0001537	Umbilical hernia
HP:0001611	Hypernasal speech
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001883	Talipes
HP:0002627	Right aortic arch with mirror image branching
HP:0002719	Recurrent infections
HP:0002901	Hypocalcemia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007382_22	Plasma free amino acid levels (adjusted for twenty other PFAAs)	2.000000e-12
GCST007385_12	Plasma free amino acid levels	3.000000e-10
GCST009391_466	Metabolite levels	7.000000e-15
GCST90002385_572	High light scatter reticulocyte count	6.000000e-10
GCST90002386_527	High light scatter reticulocyte percentage of red cells	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567511	Chromosome 22q11.2 Deletion Syndrome, Distal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression	2
fluorene-9-bisphenol	decreases expression	1
sodium arsenite	decreases expression, increases abundance, affects cotreatment	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
ochratoxin A	increases acetylation, increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Benztropine	decreases expression	1
Clozapine	decreases expression	1
Cuprizone	decreases expression	1
Doxorubicin	increases expression	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methotrexate	affects response to substance	1
Phthalic Acids	increases methylation	1
Polycyclic Aromatic Hydrocarbons	increases abundance, affects cotreatment, decreases expression	1
Selenium	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Triclosan	decreases expression	1
Copper Sulfate	decreases expression	1
1-Butanol	affects cotreatment, decreases expression, increases abundance	1
Acrylamide	decreases expression	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.