ESCO2

Summary

ESCO2 (establishment of sister chromatid cohesion N-acetyltransferase 2, HGNC:27230) is a protein-coding gene on chromosome 8p21.1, encoding N-acetyltransferase ESCO2 (Q56NI9). Acetyltransferase required for the establishment of sister chromatid cohesion. It is a selective cancer dependency (DepMap: 14.2% of cell lines).

This gene encodes a protein that may have acetyltransferase activity and may be required for the establishment of sister chromatid cohesion during the S phase of mitosis. Mutations in this gene have been associated with Roberts syndrome.

Source: NCBI Gene 157570 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Roberts-SC phocomelia syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 794 total — 85 pathogenic, 50 likely-pathogenic
• Phenotypes (HPO): 122
• Cancer dependency (DepMap): dependent in 14.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001017420

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27230
Approved symbol	ESCO2
Name	establishment of sister chromatid cohesion N-acetyltransferase 2
Location	8p21.1
Locus type	gene with protein product
Status	Approved
Aliases	EFO2
Ensembl gene	ENSG00000171320
Ensembl biotype	protein_coding
OMIM	609353
Entrez	157570

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000305188, ENST00000397418, ENST00000518262, ENST00000519637, ENST00000522378, ENST00000523566, ENST00000523910, ENST00000524293

RefSeq mRNA: 1 — MANE Select: NM_001017420 NM_001017420

CCDS: CCDS34872

Canonical transcript exons

ENST00000305188 — 11 exons

Exon	Start	End
ENSE00001230341	27803306	27805316
ENSE00001700063	27780174	27780267
ENSE00001731658	27774554	27774607
ENSE00001780905	27784000	27784057
ENSE00003513996	27791963	27792052
ENSE00003535814	27776362	27777169
ENSE00003543914	27788847	27788978
ENSE00003544183	27787885	27788002
ENSE00003581389	27775499	27775567
ENSE00003611316	27799541	27799716
ENSE00003646638	27792668	27792811

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 95.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1097 / max 331.3269, expressed in 1257 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88180	7.7020	1182
88181	1.5267	599
88179	0.8348	478
88178	0.0462	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.65	gold quality
buccal mucosa cell	CL:0002336	94.90	gold quality
secondary oocyte	CL:0000655	92.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.20	gold quality
ventricular zone	UBERON:0003053	86.94	gold quality
embryo	UBERON:0000922	85.89	gold quality
ganglionic eminence	UBERON:0004023	85.89	gold quality
bone marrow cell	CL:0002092	78.99	gold quality
stromal cell of endometrium	CL:0002255	77.06	gold quality
rectum	UBERON:0001052	76.31	gold quality
vermiform appendix	UBERON:0001154	74.61	gold quality
adrenal tissue	UBERON:0018303	73.88	gold quality
colonic epithelium	UBERON:0000397	73.09	gold quality
duodenum	UBERON:0002114	70.57	gold quality
bone marrow	UBERON:0002371	69.85	gold quality
mucosa of transverse colon	UBERON:0004991	69.69	gold quality
lymph node	UBERON:0000029	68.95	gold quality
smooth muscle tissue	UBERON:0001135	67.55	gold quality
caecum	UBERON:0001153	67.22	gold quality
testis	UBERON:0000473	66.25	gold quality
esophagus mucosa	UBERON:0002469	65.22	gold quality
right testis	UBERON:0004534	65.05	gold quality
left testis	UBERON:0004533	63.31	gold quality
islet of Langerhans	UBERON:0000006	63.27	gold quality
small intestine	UBERON:0002108	63.17	gold quality
gall bladder	UBERON:0002110	62.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	62.16	gold quality
lower esophagus mucosa	UBERON:0035834	60.66	gold quality
cortical plate	UBERON:0005343	60.44	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	130.91
E-MTAB-7249	yes	102.70
E-MTAB-6678	yes	7.85
E-ANND-3	yes	6.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF143

miRNA regulators (miRDB)

116 targeting ESCO2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 14.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 29)

• required for the establishment of sister chromatid cohesion during S phase (PMID:15821733)
• EFO1 and EFO2 are targeted to different chromosome structures to help establish or maintain sister-chromatid cohesion (PMID:15958495)
• Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: there is no phenotype-genotype correlation. (PMID:16380922)
• We used Western blot analysis to demonstrate the absence of the ESCO2-truncated protein in cells derived from both fetuses and in a lymphoblastoid cell line derived from the parents. (PMID:16775838)
• detection of an ESCO2 frameshift mutation in Roberts syndrome in a Pakistani family (PMID:18186147)
• Loss of ESCO2 acetyltransferase activity contributes to the pathogenesis of Roberts syndrome/SC phocomelia. (PMID:18411254)
• These results suggest a novel function of Esco2 in transcription repression through modulation of the chromatin structure. (PMID:18501190)
• In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in Roberts syndrome. (PMID:19574259)
• ESCO2 has an S-phase specific role in the maintenance of genome stability (PMID:19738907)
• These results demonstrated that the Staf binding site functioned as the basal transcriptional activator of the S phase-specific gene ESCO2, but other mechanisms are required for cell cycle-dependent expression. (PMID:20116366)
• the ESCO2 gene mutation responsible for developmental abnormalities maps to chromosome 8p21. (PMID:21777535)
• The Esco2 is required for double-strand break (DSB) repair, which is consistent with previous studies in Roberts syndrome(RBS) cells. (PMID:22614755)
• Data indicate that Esco1 and Esco2 contribute to distinct and separable activities of cohesin in vertebrate cells. (PMID:28847955)
• ESCO2 knockdown inhibits cell proliferation and induces apoptosis in human gastric cancer cells. (PMID:29330052)
• The analysis of ESCO2 mutants defective in MCM binding indicates that these interactions are required for proper recruitment of ESCO2 to chromatin, cohesin acetylation during DNA replication, and centromeric cohesion. (PMID:29930102)
• MCM complex couples ESCO2 with DNA replication and that the CUL4-DDB1-VPRBP complex promotes post-replicative ESCO2 degradation, presumably to suppress cohesion formation during mitosis. (PMID:30100344)
• Several lines of evidence show selective interaction of CRL4s with ESCO2 through LxG motif. (PMID:30779731)
• The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis. (PMID:31388035)
• DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated. (PMID:31935221)
• Establishment of cohesion 1 homolog 2 facilitates cell aggressive behaviors and induces poor prognosis in renal cell carcinoma. (PMID:31944408)
• Alternative catalytic residues in the active site of Esco acetyltransferases. (PMID:32555289)
• Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2. (PMID:32977150)
• ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation. (PMID:33573689)
• Effects of ESCO2 or its methylation on the prognosis, clinical characteristics, immune microenvironment, and pathogenesis of low-grade glioma. (PMID:35008004)
• Long noncoding RNA ZFPM2-AS1 regulates renal cell carcinoma progression via miR-130a-3p/ESCO2. (PMID:35258173)
• Upregulation of KAT2B and ESCO2 gene expression level in patients with rheumatoid arthritis. (PMID:36104638)
• Symmetric control of sister chromatid cohesion establishment. (PMID:36912084)
• Circular RNA METTL15/miR-374a-5p/ESCO2 axis induces colorectal cancer development. (PMID:37715994)
• ESCO2’s oncogenic role in human tumors: a pan-cancer analysis and experimental validation. (PMID:38605349)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	esco2	ENSDARG00000014685
mus_musculus	Esco2	ENSMUSG00000022034
rattus_norvegicus	Esco2	ENSRNOG00000015921
rattus_norvegicus	Esco2-ps2	ENSRNOG00000029520
rattus_norvegicus	AABR07057438.1	ENSRNOG00000033952

Paralogs (5): POLI (ENSG00000101751), POLK (ENSG00000122008), REV1 (ENSG00000135945), ESCO1 (ENSG00000141446), POLH (ENSG00000170734)

Protein

Protein identifiers

N-acetyltransferase ESCO2 — Q56NI9 (reviewed: Q56NI9)

Alternative names: Establishment factor-like protein 2, Establishment of cohesion 1 homolog 2

All UniProt accessions (5): E5RFE4, E5RFP7, E5RIE3, Q56NI9, H0YB88

UniProt curated annotations — full annotation on UniProt →

Function. Acetyltransferase required for the establishment of sister chromatid cohesion. Couples the processes of cohesion and DNA replication to ensure that only sister chromatids become paired together. In contrast to the structural cohesins, the deposition and establishment factors are required only during the S phase. Acetylates the cohesin component SMC3.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed in fetal tissues. In adult, it is expressed in thymus, placenta and small intestine.

Disease relevance. Roberts-SC phocomelia syndrome (RBS) [MIM:268300] An autosomal recessive disorder characterized by pre- and postnatal growth retardation, intellectual disability, microcephaly, bilateral cleft lip and cleft palate, and mesomelic symmetric limb reduction. Severely affected infants may be stillborn or die shortly after birth. Patient chromosomes have a lack of cohesion involving heterochromatic C-banding regions around centromeres and the heterochromatin regions on the 1, 9, 16, and Y chromosomes. These findings are referred to as premature centromere separation (PCS) and heterochromatin repulsion (HR), and they are important for the diagnosis of the syndrome. The disease is caused by variants affecting the gene represented in this entry. Juberg-Hayward syndrome (JHS) [MIM:216100] An autosomal recessive syndrome characterized by cleft lip/palate, microcephaly, ptosis, hypoplasia or aplasia of thumbs, short stature, dislocation of radial head, and fusion of humerus and radius leading to elbow restriction. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal region seems to be responsible for association with chromosomes, thus excluding any involvement of the Zn finger in this process.

Similarity. Belongs to the acetyltransferase family. ECO subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q56NI9-1	1	yes
Q56NI9-2	2

RefSeq proteins (1): NP_001017420* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028005	AcTrfase_ESCO_Znf_dom	Domain
IPR028009	ESCO_Acetyltransf_dom	Domain

Pfam: PF13878, PF13880

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + acetyl-CoA = N(6)-acetyl-L-lysyl-[protein] + CoA + H(+) (RHEA:45948)

UniProt features (18 total): modified residue 6, sequence variant 4, splice variant 2, region of interest 2, compositionally biased region 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q56NI9-F1	58.81	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 312, 512, 29, 75, 223, 244

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2468052	Establishment of Sister Chromatid Cohesion

MSigDB gene sets: 496 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, PATIL_LIVER_CANCER, chr8p21, GOBP_PROTEIN_ACETYLATION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_SISTER_CHROMATID_COHESION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_DNA_DAMAGE_RESPONSE, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, FISCHER_DREAM_TARGETS

GO Biological Process (8): hematopoietic progenitor cell differentiation (GO:0002244), regulation of DNA replication (GO:0006275), double-strand break repair (GO:0006302), chromosome segregation (GO:0007059), sister chromatid cohesion (GO:0007062), mitotic sister chromatid cohesion (GO:0007064), post-translational protein acetylation (GO:0034421), protein localization to chromatin (GO:0071168)

GO Molecular Function (9): L-lysine N6-acetyltransferase activity, acting on acetyl phosphate as donor (GO:0004468), N-acetyltransferase activity (GO:0008080), zinc ion binding (GO:0008270), acetyltransferase activity (GO:0016407), protein-lysine-acetyltransferase activity (GO:0061733), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), metal ion binding (GO:0046872)

GO Cellular Component (10): chromatin (GO:0000785), XY body (GO:0001741), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), pericentric heterochromatin (GO:0005721), Golgi apparatus (GO:0005794), chromocenter (GO:0010369), cell junction (GO:0030054), site of double-strand break (GO:0035861)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
S Phase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell cycle process	2
intracellular membrane-bounded organelle	2
intracellular membraneless organelle	2
hemopoiesis	1
cell differentiation	1
DNA replication	1
regulation of DNA metabolic process	1
DNA repair	1
chromosome organization	1
sister chromatid cohesion	1
protein acetylation	1
post-translational protein modification	1
protein localization to chromosome	1
L-amino-acid N-acetyltransferase activity	1
acetyltransferase activity	1
transition metal ion binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
protein N-acetyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
cation binding	1
chromosome	1
sex chromosome	1
condensed chromatin of inactivated sex chromosome	1
nuclear lumen	1
chromosome, centromeric region	1
heterochromatin	1
cytoplasm	1
endomembrane system	1
site of DNA damage	1

Protein interactions and networks

STRING

2368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESCO2	SMC3	Q9UQE7	973
ESCO2	PDS5A	Q29RF7	959
ESCO2	WAPL	Q7Z5K2	956
ESCO2	CHTF18	Q8WVB6	922
ESCO2	RAD21	O60216	895
ESCO2	NIPBL	Q6KC79	879
ESCO2	GLYATL1	Q969I3	869
ESCO2	NAT10	Q9H0A0	839
ESCO2	DSCC1	Q9BVC3	826
ESCO2	MAU2	Q9Y6X3	825
ESCO2	CHTF8	P0CG13	822
ESCO2	ESPL1	Q14674	813
ESCO2	HGSNAT	Q68CP4	802
ESCO2	NAA10	P41227	793
ESCO2	SMC1A	Q14683	772

IntAct

49 interactions, top by confidence:

A	B	Type	Score
ESCO2	PICK1	psi-mi:“MI:0915”(physical association)	0.560
RABEP1	ESCO2	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	ESCO2	psi-mi:“MI:0915”(physical association)	0.560
FXR1	ESCO2	psi-mi:“MI:0915”(physical association)	0.560
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Cct2	OSBPL9	psi-mi:“MI:0914”(association)	0.350
Poc1a	SQSTM1	psi-mi:“MI:0914”(association)	0.350
MATR3	BCLAF3	psi-mi:“MI:0914”(association)	0.350
Lrrcc1	CCDC14	psi-mi:“MI:0914”(association)	0.350
NCAPD3	SMC2	psi-mi:“MI:0914”(association)	0.350
S100A4	BBX	psi-mi:“MI:0914”(association)	0.350
USF1	MAP3K4	psi-mi:“MI:0914”(association)	0.350
YEATS4	ING3	psi-mi:“MI:0914”(association)	0.350
RPGRIP1L	KIF2A	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CBX8	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
ZNF677	ZNF320	psi-mi:“MI:0914”(association)	0.350
ANAPC15	U2SURP	psi-mi:“MI:0914”(association)	0.350
GAGE2E	WDR46	psi-mi:“MI:0914”(association)	0.350
H2AJ	WDR46	psi-mi:“MI:0914”(association)	0.350
UQCR11	WDR46	psi-mi:“MI:0914”(association)	0.350
NDC80	WDR46	psi-mi:“MI:0914”(association)	0.350
CKAP2	WDR46	psi-mi:“MI:0914”(association)	0.350
GNL2	POLR1G	psi-mi:“MI:0914”(association)	0.350
PSENEN	KIF1C	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): ESCO2 (Affinity Capture-RNA), ESCO2 (Affinity Capture-RNA), ESCO2 (Proximity Label-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), ESCO2 (Affinity Capture-MS), MCM2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2L7I0, A0A1L8G2K9, A0A1P8AW69, A5D979, A8K979, B3H578, B4R4H1, D3ZVU1, F4HTH8, F4HXQ7, F4I8S3, F6UH96, G3X912, O64571, P0DKJ8, P62283, P62285, P62286, P62287, P62288, P62289, P62290, P62293, P62294, Q0IGK1, Q2PS26, Q56NI9, Q5QGU6, Q60GC1, Q6DJS0, Q6DRC5, Q6NYJ3, Q6PF04, Q7ZXG4, Q8BMI4, Q8BP27, Q8CIB9, Q8IZT6, Q8N4S0, Q94F87

Diamond homologs: A7UL74, P43605, Q56NI9, Q6C668, Q8CIB9, A1JNY3, A1RMZ5, A1S8M3, A3D147, A3N148, A4TPK8, A5F5Y1, A6WRW5, A7FLI9, A7MEN4, A9L0T3, B0BPX9, B8F542, C3LQ59, O42917, Q086K1, Q12Q05, Q1C4D9, Q1CLD4, Q487H6, Q5FWF5, Q5SPR8, Q65TG8, Q66DZ7, Q69Z69, Q6D1H8, Q7MID6, Q87MB4, Q8DBI7, Q8ZBZ9, Q9JJN0, Q9KPS5, Q9Y253, Q9VS50

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	85
Likely pathogenic	50
Uncertain significance	230
Likely benign	323
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071815	NM_001017420.3(ESCO2):c.775C>T (p.Gln259Ter)	Pathogenic
1071994	NM_001017420.3(ESCO2):c.166_170del (p.Val56fs)	Pathogenic
1072358	NM_001017420.3(ESCO2):c.457dup (p.Arg153fs)	Pathogenic
1073383	NM_001017420.3(ESCO2):c.609dup (p.Thr204fs)	Pathogenic
1073674	NM_001017420.3(ESCO2):c.133_143del (p.Glu45fs)	Pathogenic
1075786	NM_001017420.3(ESCO2):c.503del (p.Asn168fs)	Pathogenic
1075906	NC_000008.10:g.(?27641507)(27641584_?)del	Pathogenic
1076003	NM_001017420.3(ESCO2):c.1353+1del	Pathogenic
1332853	NM_001017420.3(ESCO2):c.1673+1G>A	Pathogenic
1373535	NM_001017420.3(ESCO2):c.102_103del (p.His34fs)	Pathogenic
1375819	NM_001017420.3(ESCO2):c.152_153del (p.Gln51fs)	Pathogenic
1376646	NM_001017420.3(ESCO2):c.376dup (p.Met126fs)	Pathogenic
1383622	NM_001017420.3(ESCO2):c.273_283del (p.Trp92fs)	Pathogenic
1391159	NM_001017420.3(ESCO2):c.861+1dup	Pathogenic
1436571	NM_001017420.3(ESCO2):c.744_747del (p.Ser250fs)	Pathogenic
1451780	NM_001017420.3(ESCO2):c.759_760insGA (p.Thr254fs)	Pathogenic
1452680	NM_001017420.3(ESCO2):c.897dup (p.Lys300Ter)	Pathogenic
1455776	NM_001017420.3(ESCO2):c.269dup (p.Asn90fs)	Pathogenic
1456491	NM_001017420.3(ESCO2):c.751G>T (p.Glu251Ter)	Pathogenic
1456847	NM_001017420.3(ESCO2):c.1214_1215dup (p.Gln406fs)	Pathogenic
1457066	NM_001017420.3(ESCO2):c.1246_1252dup (p.Ile418fs)	Pathogenic
1457768	NM_001017420.3(ESCO2):c.417del (p.Lys139fs)	Pathogenic
1457982	NM_001017420.3(ESCO2):c.485del (p.Ser162fs)	Pathogenic
1736	NM_001017420.3(ESCO2):c.505C>T (p.Arg169Ter)	Pathogenic
1737	NM_001017420.3(ESCO2):c.751dup (p.Glu251fs)	Pathogenic
1738	NM_001017420.3(ESCO2):c.760dup (p.Thr254fs)	Pathogenic
1740	NM_001017420.3(ESCO2):c.604C>T (p.Gln202Ter)	Pathogenic
1992937	NM_001017420.3(ESCO2):c.1492A>T (p.Lys498Ter)	Pathogenic
2000703	NM_001017420.3(ESCO2):c.1554T>A (p.Cys518Ter)	Pathogenic
2008551	NM_001017420.3(ESCO2):c.843_846del (p.Asn281fs)	Pathogenic

SpliceAI

2046 predictions. Top by Δscore:

Variant	Effect	Δscore
8:27772511:A:AC	donor_gain	1.0000
8:27772512:C:CC	donor_gain	1.0000
8:27772512:CCG:C	donor_gain	1.0000
8:27774606:AG:A	donor_loss	1.0000
8:27774608:G:C	donor_loss	1.0000
8:27775493:TTTTA:T	acceptor_loss	1.0000
8:27775494:TTTAG:T	acceptor_loss	1.0000
8:27775495:TTA:T	acceptor_loss	1.0000
8:27775496:TA:T	acceptor_loss	1.0000
8:27775497:A:AG	acceptor_gain	1.0000
8:27775497:A:AT	acceptor_loss	1.0000
8:27775498:G:GC	acceptor_loss	1.0000
8:27775498:G:GG	acceptor_gain	1.0000
8:27775498:GGA:G	acceptor_gain	1.0000
8:27775541:G:GT	donor_gain	1.0000
8:27775564:ACAG:A	donor_gain	1.0000
8:27775564:ACAGG:A	donor_loss	1.0000
8:27775565:CAG:C	donor_loss	1.0000
8:27775566:AGGT:A	donor_loss	1.0000
8:27775567:GGTG:G	donor_loss	1.0000
8:27775568:G:GC	donor_loss	1.0000
8:27775569:T:A	donor_loss	1.0000
8:27775578:GCCT:G	donor_gain	1.0000
8:27780263:GACAA:G	donor_gain	1.0000
8:27780268:G:GG	donor_gain	1.0000
8:27788001:TC:T	donor_gain	1.0000
8:27788003:G:GG	donor_gain	1.0000
8:27788839:A:AG	acceptor_gain	1.0000
8:27788840:A:G	acceptor_gain	1.0000
8:27788843:ATAG:A	acceptor_gain	1.0000

AlphaMissense

3997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:27792782:G:T	G490W	0.999
8:27792783:G:A	G490E	0.999
8:27799647:T:A	I535K	0.999
8:27799658:T:A	W539R	0.999
8:27799658:T:C	W539R	0.999
8:27799704:T:A	V554D	0.999
8:27803350:C:A	A573E	0.999
8:27803353:T:C	F574S	0.999
8:27803383:T:C	F584S	0.999
8:27803386:C:A	A585E	0.999
8:27788880:T:C	C389R	0.998
8:27792782:G:A	G490R	0.998
8:27792782:G:C	G490R	0.998
8:27799640:T:C	C533R	0.998
8:27799642:T:G	C533W	0.998
8:27799643:G:T	G534W	0.998
8:27799644:G:A	G534E	0.998
8:27799647:T:G	I535R	0.998
8:27799678:A:C	R545S	0.998
8:27799678:A:T	R545S	0.998
8:27799692:C:A	A550E	0.998
8:27799701:T:C	L553P	0.998
8:27803352:T:C	F574L	0.998
8:27803354:T:A	F574L	0.998
8:27803354:T:G	F574L	0.998
8:27803362:C:A	P577Q	0.998
8:27803374:G:A	G581D	0.998
8:27803394:T:G	Y588D	0.998
8:27803412:T:C	F594L	0.998
8:27803414:C:A	F594L	0.998

dbSNP variants (sampled 300 via entrez): RS1000004034 (8:27773632 G>A,T), RS1000043745 (8:27782584 T>C), RS1000087509 (8:27817325 C>T), RS1000183509 (8:27804327 C>A,T), RS1000415411 (8:27817043 A>G), RS1000418833 (8:27816261 T>C), RS1000433807 (8:27785907 T>C), RS1000522258 (8:27806009 C>T), RS1000619029 (8:27812300 G>A,T), RS1000736125 (8:27770854 A>G), RS1000806072 (8:27817483 CTTT>C), RS1000808695 (8:27810673 A>C), RS1000815622 (8:27812406 T>C,G), RS1000838744 (8:27792825 G>C,T), RS1000852495 (8:27775061 C>T)

Disease associations

OMIM: gene MIM:609353 | disease phenotypes: MIM:216100, MIM:268300, MIM:269000, MIM:143890

GenCC curated gene-disease

Disease	Classification	Inheritance
Roberts-SC phocomelia syndrome	Definitive	Autosomal recessive
Roberts syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Roberts-SC phocomelia syndrome	Definitive	AR

Mondo (5): Juberg-Hayward syndrome (MONDO:0008992), Roberts-SC phocomelia syndrome (MONDO:0100253), hereditary breast ovarian cancer syndrome (MONDO:0003582), hypercholesterolemia, familial, 1 (MONDO:0007750), (MONDO:0009997)

Orphanet (4): Juberg-Hayward syndrome (Orphanet:2319), Roberts syndrome (Orphanet:3103), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000040	Long penis
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000113	Polycystic kidney dysplasia
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000387	Absent earlobe
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000470	Short neck
HP:0000476	Cystic hygroma
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
C537690	Juberg Hayward syndrome (supp.)
C535687	Roberts Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Cyclosporine	decreases expression	3
arsenite	affects expression, affects binding, decreases reaction	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	affects expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
polyhexamethyleneguanidine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	affects expression	1
Arsenic	increases abundance, increases expression	1
Azathioprine	decreases expression	1

Cellosaurus cell lines

9 cell lines: 5 transformed cell line, 4 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5R39	GM21871	Transformed cell line	Female
CVCL_7660	GM20466	Transformed cell line	Female
CVCL_7661	GM20467	Finite cell line	Female
CVCL_7663	GM21872	Finite cell line	Female
CVCL_D339	GM21873	Finite cell line	Female
CVCL_XX25	VU1199-F	Finite cell line	Male
CVCL_XX26	VU1199-F SV40	Transformed cell line	Male
CVCL_XX27	VU1199-F SV40+GFP-ESCO2	Transformed cell line	Male
CVCL_XX28	VU1199-F SV40+V5-ESCO2	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer