ERCC6L2

Summary

ERCC6L2 (ERCC excision repair 6 like 2, HGNC:26922) is a protein-coding gene on chromosome 9q22.32, encoding DNA excision repair protein ERCC-6-like 2 (Q5T890). Promotes double-strand break (DSB) end-joining and facilitates programmed recombination by controlling how DNA ends are joined in a spatially oriented manner during repair.

This gene encodes a member of the Snf2 family of helicase-like proteins. The encoded protein may play a role in DNA repair and mitochondrial function. Mutations in this gene have been associated with bone marrow failure syndrome 2. Alternatively spliced transcript variants that encode different protein isoforms have been described.

Source: NCBI Gene 375748 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pancytopenia-developmental delay syndrome (Definitive, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 1,682 total — 41 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 10
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26922
Approved symbol	ERCC6L2
Name	ERCC excision repair 6 like 2
Location	9q22.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37706, RAD26L, HEBO
Ensembl gene	ENSG00000182150
Ensembl biotype	protein_coding
OMIM	615667
Entrez	375748

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 13 protein_coding, 9 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000288985, ENST00000402838, ENST00000426805, ENST00000456993, ENST00000466840, ENST00000479391, ENST00000653324, ENST00000653738, ENST00000659728, ENST00000661047, ENST00000665077, ENST00000668220, ENST00000670016, ENST00000682148, ENST00000682394, ENST00000682748, ENST00000682951, ENST00000682983, ENST00000683128, ENST00000683156, ENST00000683176, ENST00000683227, ENST00000683230, ENST00000683350, ENST00000683937, ENST00000683991, ENST00000715566, ENST00000922956, ENST00000922957, ENST00000957783

RefSeq mRNA: 6 — MANE Select: NM_020207 NM_001010895, NM_001375291, NM_001375292, NM_001375293, NM_001375294, NM_020207

CCDS: CCDS35072, CCDS94442, CCDS94443

Canonical transcript exons

ENST00000653738 — 19 exons

Exon	Start	End
ENSE00001221642	96004520	96004701
ENSE00001646322	95966562	95966714
ENSE00003464760	95928079	95928150
ENSE00003491297	95897849	95897971
ENSE00003503418	95922305	95922418
ENSE00003512758	95907078	95907271
ENSE00003531377	95955914	95956013
ENSE00003532861	95941454	95941549
ENSE00003593181	95916227	95916434
ENSE00003632742	95880869	95881293
ENSE00003638166	95923260	95923379
ENSE00003644327	95915668	95915829
ENSE00003649470	95978061	95978215
ENSE00003670349	95970576	95970656
ENSE00003670593	95928719	95928864
ENSE00003690314	95921175	95921315
ENSE00003858951	95971933	95973088
ENSE00003881735	96012225	96018447
ENSE00003901022	95875691	95876084

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 92.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8374 / max 73.7951, expressed in 1747 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97513	7.0650	1670
97514	2.7724	1290

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	92.99	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.23	gold quality
endothelial cell	CL:0000115	91.89	gold quality
calcaneal tendon	UBERON:0003701	90.24	gold quality
germinal epithelium of ovary	UBERON:0001304	90.21	gold quality
sural nerve	UBERON:0015488	89.65	gold quality
tibia	UBERON:0000979	89.39	gold quality
adrenal tissue	UBERON:0018303	89.26	gold quality
tendon	UBERON:0000043	88.79	gold quality
middle temporal gyrus	UBERON:0002771	87.32	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.91	gold quality
myocardium	UBERON:0002349	86.85	silver quality
parietal pleura	UBERON:0002400	86.83	gold quality
visceral pleura	UBERON:0002401	86.67	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.45	silver quality
pancreatic ductal cell	CL:0002079	86.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.97	gold quality
lower lobe of lung	UBERON:0008949	85.92	gold quality
colonic epithelium	UBERON:0000397	85.89	gold quality
left ventricle myocardium	UBERON:0006566	85.70	silver quality
tendon of biceps brachii	UBERON:0008188	85.52	silver quality
upper arm skin	UBERON:0004263	85.24	gold quality
palpebral conjunctiva	UBERON:0001812	84.93	gold quality
corpus callosum	UBERON:0002336	84.68	gold quality
superficial temporal artery	UBERON:0001614	84.66	gold quality
pigmented layer of retina	UBERON:0001782	84.33	gold quality
caput epididymis	UBERON:0004358	84.19	gold quality
jejunal mucosa	UBERON:0000399	83.92	gold quality
epithelium of nasopharynx	UBERON:0001951	83.85	gold quality
medial globus pallidus	UBERON:0002477	83.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting ERCC6L2, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-378A-5P	99.65	66.33	1311

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• These observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function. (PMID:24507776)
• Hebo is ubiquitously expressed, localized in the nucleus, and rapidly recruited to DNAdsb’s in an NBS1-dependent manner. (PMID:27185855)
• We report 2 cases of bone marrow failure with no extra-hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described. (PMID:28815563)
• ERCC6L2-associated disorder has recently been described. We identified an additional case through whole-exome sequencing. At the age of 9 years, the patient underwent whole exome sequencing and was discovered to have a homozygous stop mutation in ERCC6L2 (NCBI RefSeq NG_034107.1), c.1687C>T (p.Arg563*). (PMID:29633571)
• The inherited bone marrow failure syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect (PMID:29987015)
• Study found that rs591486 was associated with an increased risk of amyotrophic lateral sclerosis. Moreover, we found that rs591486 ERCC6L2 influences the age of onset of amyotrophic lateral sclerosis with limb onset. (PMID:30879219)
• We report a direct association of a homozygous truncating germ line mutation in ERCC6L2 with a specific high-risk leukemia subtype (PMID:30936069)
• Functional Radiogenetic Profiling Implicates ERCC6L2 in Non-homologous End Joining. (PMID:32846126)
• Microdeletion of 9q22.3: A patient with minimal deletion size associated with a severe phenotype. (PMID:33960642)
• Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment. (PMID:36156210)
• ERCC6L2-related disease: a novel entity of bone marrow failure disorder with high risk of clonal evolution. (PMID:36790458)
• ERCC6L2 mitigates replication stress and promotes centromere stability. (PMID:37014751)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

DNA excision repair protein ERCC-6-like 2 — Q5T890 (reviewed: Q5T890)

Alternative names: DNA repair and recombination protein RAD26-like, Excision repair cross-complementation group 6-like 2

All UniProt accessions (17): Q5T890, A0A590UJ12, A0A590UJA1, A0A590UJI9, A0A590UJK0, A0A590UJV1, A0A5F9UKL4, A0A804HJ75, A0A804HJC4, A0A804HK79, A0A804HL79, A0AAA9Y8Y6, A0AAQ5BIG0, F2Z2R4, H0Y3T7, S4R327, X6RE28

UniProt curated annotations — full annotation on UniProt →

Function. Promotes double-strand break (DSB) end-joining and facilitates programmed recombination by controlling how DNA ends are joined in a spatially oriented manner during repair. Also plays a role in DNA repair by restricting DNA end resection in double strand break (DSB) repair. Facilitates replication of complex DNA regions and regulates the maintenance of chromatin structure.

Subunit / interactions. Interacts with NEK6. Interacts (via an atypical PIP-box) with PCNA; this interaction facilitates cenrtomeric localization of ERCC6L2. Interacts with CYREN; this interaction is DNA independent. Interacts with XRCC6 and XRCC5.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Mitochondrion. Chromosome. Centromere.

Tissue specificity. Expressed in bone marrow (at protein level).

Post-translational modifications. Phosphorylated by NEK6.

Disease relevance. Bone marrow failure syndrome 2 (BMFS2) [MIM:615715] An autosomal recessive disorder characterized by trilineage bone marrow failure, bone marrow hypocellularity, learning difficulties, and microcephaly. Insufficient hematopoiesis results in peripheral blood cytopenias, affecting myeloid, erythroid and megakaryocyte lines. Cutaneous features and increased chromosome breakage are not features. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The atypical PIP-box motif mediates interaction with PCNA. The helicase C-terminal domaine drives nuclear localization and recruitment to damaged sites.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5T890-4	3	yes
Q5T890-1	1
Q5T890-2	2, RAD26L

RefSeq proteins (6): NP_001010895, NP_001362220, NP_001362221, NP_001362222, NP_001362223, NP_064592* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029256	Heliccase-ass-bd	Domain
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR049730	SNF2/RAD54-like_C	Domain
IPR050496	SNF2_RAD54_helicase_repair	Family
IPR057931	RHH_ERCC6L2	Domain
IPR058052	DEXHc_ERCC6L2	Domain

Pfam: PF00176, PF00271, PF14773, PF25806

UniProt features (35 total): compositionally biased region 6, modified residue 4, strand 4, region of interest 4, splice variant 3, mutagenesis site 3, domain 2, helix 2, short sequence motif 2, chain 1, binding site 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6HQ9	X-RAY DIFFRACTION	1.98
8COB	X-RAY DIFFRACTION	2.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T890-F1	58.11	0.10

Functional residue map

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

Ligand- & substrate-binding residues (1): 159–166

Post-translational modifications (4): 991, 994, 1384, 1387

Mutagenesis-validated functional residues (3):

Position	Phenotype
798	affects centromeric localization. affects localization at sites of dna replication.
804	affects centromeric localization. affects localization at sites of dna replication.
806	affects centromeric localization. affects localization at sites of dna replication.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 158 (showing top): GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOCC_MICROTUBULE_ORGANIZING_CENTER, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, GOCC_CENTROSOME, GRE_C, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_DNA_DAMAGE_RESPONSE, TGACATY_UNKNOWN, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, chr9q22, ZHANG_BREAST_CANCER_PROGENITORS_UP, GOBP_CELLULAR_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN

GO Biological Process (5): DNA damage response (GO:0006974), cellular response to reactive oxygen species (GO:0034614), interstrand cross-link repair (GO:0036297), double-strand break repair via classical nonhomologous end joining (GO:0097680), DNA repair (GO:0006281)

GO Molecular Function (7): DNA binding (GO:0003677), helicase activity (GO:0004386), ATP binding (GO:0005524), hydrolase activity (GO:0016787), protein kinase binding (GO:0019901), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), centrosome (GO:0005813), protein-containing complex (GO:0032991), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytosol (GO:0005829), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular membrane-bounded organelle	2
cytoplasm	2
intracellular membraneless organelle	2
cellular response to stress	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
DNA repair	1
double-strand break repair via nonhomologous end joining	1
DNA metabolic process	1
DNA damage response	1
nucleic acid binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
ATP-dependent activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
chromosomal region	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cellular_component	1
nuclear lumen	1

Protein interactions and networks

STRING

2681 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERCC6L2	ELOF1	P60002	568
ERCC6L2	CYREN	Q9BWK5	560
ERCC6L2	SAMD9L	Q8IVG5	482
ERCC6L2	SAMD9	Q5K651	480
ERCC6L2	NHEJ1	Q9H9Q4	467
ERCC6L2	PAXX	Q9BUH6	456
ERCC6L2	WRN	Q14191	455
ERCC6L2	SHLD1	Q8IYI0	435
ERCC6L2	DNAJC21	Q5F1R6	415
ERCC6L2	LIG4	P49917	409
ERCC6L2	SPIDR	Q14159	406
ERCC6L2	TXNDC17	Q9BRA2	395
ERCC6L2	TGFBR1	P36897	392
ERCC6L2	TGFBR2	P37173	391
ERCC6L2	BLM	P54132	384

IntAct

12 interactions, top by confidence:

A	B	Type	Score
ERCC6L2	CYREN	psi-mi:“MI:0915”(physical association)	0.560
ERCC6L2	TCP11L1	psi-mi:“MI:0915”(physical association)	0.560
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
ERCC6L2	RPL24	psi-mi:“MI:0915”(physical association)	0.400
ERCC6L2	HNRNPA1L2	psi-mi:“MI:0915”(physical association)	0.400
PB2	SEC15L3	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
CYREN	ERCC6L2	psi-mi:“MI:0915”(physical association)	0.000
ERCC6L2	TCP11L1	psi-mi:“MI:0915”(physical association)	0.000
TCP11L1	ERCC6L2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): ERCC6L2 (Two-hybrid), ERCC6L2 (Affinity Capture-RNA), ERCC6L2 (Two-hybrid), ERCC6L2 (Two-hybrid), ERCC6L2 (Proximity Label-MS), ERCC6L2 (Proximity Label-MS), ERCC6L2 (Affinity Capture-MS), RPL8 (Cross-Linking-MS (XL-MS)), ERCC6L2 (Affinity Capture-MS), ERCC6L2 (Affinity Capture-RNA), ERCC6L2 (Two-hybrid), ERCC6L2 (Reconstituted Complex)

ESM2 similar proteins: A2BGR3, A3KFM7, A3KMI0, A3KMX0, A4IHD2, A6QQR4, B0R061, D3Z9Z9, D3ZA12, E1B7X9, E7F1C4, F4IV99, F4J9M5, F4JTF6, F4K128, F8VPZ5, G5EDG2, O14139, O42861, O97159, P32657, P32863, P38144, P40352, P87114, Q03468, Q04692, Q22516, Q2NKX8, Q5FWR0, Q5T890, Q60848, Q60EX7, Q6P158, Q6P5D3, Q75AA7, Q7F2E4, Q8BHK9, Q8TD26, Q8W103

Diamond homologs: A0A0P0WGX7, A2A8L1, A2BGR3, A3KFM7, A6QQR4, A7Z019, A9X4T1, B0R0I6, B0XPE7, B3NAN8, B4GS98, B5BT18, B5DE69, B6ZLK2, D3Z9Z9, D3ZA12, D3ZD32, E1B7X9, F1Q8K0, F4I2H2, F4IV45, F4J9M5, F4JY24, F4K128, F4KBP5, F8VPZ5, G5EBZ4, G5EF53, O12944, O13682, O14139, O14646, O14981, O43065, O76460, P0CO16, P0CO17, P28370, P31380, P32333

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1682 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	16
Uncertain significance	992
Likely benign	562
Benign	32

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1174151	NM_020207.7(ERCC6L2):c.3409_3410del (p.Met1137fs)	Pathogenic
125449	NM_020207.7(ERCC6L2):c.1930C>T (p.Arg644Ter)	Pathogenic
125450	NM_020207.7(ERCC6L2):c.1203_1206del (p.Thr402fs)	Pathogenic
1349834	NM_020207.7(ERCC6L2):c.3674+1G>A	Pathogenic
1353805	NM_020207.7(ERCC6L2):c.1654C>T (p.Arg552Ter)	Pathogenic
1390409	NM_020207.7(ERCC6L2):c.1987C>T (p.Arg663Ter)	Pathogenic
1415116	NM_020207.7(ERCC6L2):c.153dup (p.Ala52fs)	Pathogenic
1427739	NM_020207.7(ERCC6L2):c.3570_3574dup (p.Pro1192fs)	Pathogenic
1452306	NM_020207.7(ERCC6L2):c.1333dup (p.Tyr445fs)	Pathogenic
1954899	NM_020207.7(ERCC6L2):c.1137_1138insAGTCTTCT (p.Leu380fs)	Pathogenic
2091242	NM_020207.7(ERCC6L2):c.2733_2734del (p.Arg913fs)	Pathogenic
2426526	NC_000009.11:g.(?98690981)(98691166_?)del	Pathogenic
2634703	NM_020207.7(ERCC6L2):c.1220_1221del (p.Glu407fs)	Pathogenic
2696334	NM_020207.7(ERCC6L2):c.3538_3541del (p.Lys1180fs)	Pathogenic
2782050	NM_020207.7(ERCC6L2):c.31G>T (p.Glu11Ter)	Pathogenic
2797877	NM_020207.7(ERCC6L2):c.2710_2716del (p.Ile904fs)	Pathogenic
2813205	NM_020207.7(ERCC6L2):c.3106_3107del (p.Gln1036fs)	Pathogenic
2850942	NM_020207.7(ERCC6L2):c.3325del (p.Asp1109fs)	Pathogenic
2902416	NM_020207.7(ERCC6L2):c.982_1006del (p.Tyr328fs)	Pathogenic
2914794	NM_020207.7(ERCC6L2):c.1528dup (p.Met510fs)	Pathogenic
2957778	NM_020207.7(ERCC6L2):c.3415C>T (p.Arg1139Ter)	Pathogenic
2967554	NM_020207.7(ERCC6L2):c.3295del (p.Val1099fs)	Pathogenic
2969089	NM_020207.7(ERCC6L2):c.168T>G (p.Tyr56Ter)	Pathogenic
2969532	NM_020207.7(ERCC6L2):c.2836C>T (p.Arg946Ter)	Pathogenic
2998937	NM_020207.7(ERCC6L2):c.3404dup (p.Asn1135fs)	Pathogenic
3003841	NM_020207.7(ERCC6L2):c.901G>T (p.Gly301Ter)	Pathogenic
3654493	NM_020207.7(ERCC6L2):c.2467C>T (p.Gln823Ter)	Pathogenic
3674511	NM_020207.7(ERCC6L2):c.3022G>T (p.Glu1008Ter)	Pathogenic
3692630	NM_020207.7(ERCC6L2):c.-8del	Pathogenic
3727032	NM_020207.7(ERCC6L2):c.1703_1704del (p.Lys568fs)	Pathogenic

SpliceAI

2711 predictions. Top by Δscore:

Variant	Effect	Δscore
9:95880867:A:AG	acceptor_gain	1.0000
9:95880868:G:GG	acceptor_gain	1.0000
9:95880868:GAC:G	acceptor_gain	1.0000
9:95881033:G:GT	donor_gain	1.0000
9:95897967:AAAAG:A	donor_loss	1.0000
9:95897969:AAGGT:A	donor_loss	1.0000
9:95897970:AGG:A	donor_loss	1.0000
9:95897971:GGT:G	donor_loss	1.0000
9:95897972:GT:G	donor_loss	1.0000
9:95897973:T:A	donor_loss	1.0000
9:95907112:A:AG	acceptor_gain	1.0000
9:95907114:A:AG	acceptor_gain	1.0000
9:95907114:AACT:A	acceptor_gain	1.0000
9:95907114:AACTG:A	acceptor_gain	1.0000
9:95907115:A:G	acceptor_gain	1.0000
9:95915659:A:AG	acceptor_gain	1.0000
9:95915660:C:G	acceptor_gain	1.0000
9:95915664:ATAGT:A	acceptor_loss	1.0000
9:95915665:T:G	acceptor_gain	1.0000
9:95915666:A:AG	acceptor_gain	1.0000
9:95915666:AGTTT:A	acceptor_gain	1.0000
9:95915667:G:GA	acceptor_gain	1.0000
9:95915667:GT:G	acceptor_gain	1.0000
9:95915667:GTT:G	acceptor_gain	1.0000
9:95915667:GTTT:G	acceptor_gain	1.0000
9:95915667:GTTTG:G	acceptor_gain	1.0000
9:95915807:G:GT	donor_gain	1.0000
9:95915825:GACTG:G	donor_gain	1.0000
9:95915827:CTGGT:C	donor_loss	1.0000
9:95915830:G:GG	donor_gain	1.0000

AlphaMissense

10318 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000028693 (9:95967683 C>T), RS1000038669 (9:95967514 A>T), RS1000038914 (9:95922314 C>T), RS1000049098 (9:96010831 T>C), RS1000064521 (9:95903285 C>T), RS1000064827 (9:95987321 C>T), RS1000088933 (9:95918138 A>C), RS1000097738 (9:95964493 C>G,T), RS1000121556 (9:95917862 T>C), RS1000123556 (9:96028497 G>A), RS1000125826 (9:95880767 A>G), RS1000148164 (9:95961505 A>G), RS1000183845 (9:95878017 G>A), RS1000213921 (9:95959957 A>T), RS1000223041 (9:95954325 T>C,G)

Disease associations

OMIM: gene MIM:615667 | disease phenotypes: MIM:615715, MIM:245590

GenCC curated gene-disease

Disease	Classification	Inheritance
pancytopenia-developmental delay syndrome	Definitive	Autosomal recessive

Mondo (6): pancytopenia-developmental delay syndrome (MONDO:0014317), pancytopenia (MONDO:0001529), thrombocytopenia (MONDO:0002049), hereditary neoplastic syndrome (MONDO:0015356), growth hormone insensitivity with immune dysregulation 1, autosomal recessive (MONDO:0100211), premature menopause (MONDO:0001119)

Orphanet (3): Pancytopenia-developmental delay syndrome (Orphanet:401764), Inherited cancer-predisposing syndrome (Orphanet:140162), Laron syndrome with immunodeficiency (Orphanet:220465)

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000992	Cutaneous photosensitivity
HP:0001319	Neonatal hypotonia
HP:0001873	Thrombocytopenia
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0003621	Juvenile onset
HP:0005528	Bone marrow hypocellularity
HP:0025708	Early young adult onset

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003600_1	Parkinson’s disease (pesticide exposure interaction)	2.000000e-06
GCST003996_48	Monobrow	1.000000e-13
GCST010988_399	Adult body size	1.000000e-08
GCST011140_8	Glucagon levels in response to oral glucose tolerance test (decremental area under the curve for 0-30 minutes)	1.000000e-06
GCST90011900_216	Serum alkaline phosphatase levels	2.000000e-08
GCST90020028_385	Hip circumference adjusted for BMI	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007840	pesticide exposure measurement
EFO:0007906	synophrys measurement
EFO:0008463	glucagon measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010198	Pancytopenia	C15.378.243.875
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C537871	Laron syndrome type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs238	ERCC6L2	3	0.00	1	hydrochlorothiazide
rs689979	ERCC6L2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	5
trichostatin A	affects cotreatment, decreases expression, affects expression	3
Cadmium Chloride	increases abundance, increases expression, decreases expression	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM40	HAP1 ERCC6L2 (-) 1	Cancer cell line	Male
CVCL_XN51	HAP1 ERCC6L2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00000597	PHASE3	COMPLETED	Multi-Center Trial of Anti-Thymocyte Globulin in Treatment of Aplastic Anemia and Other Hematologic Disorders
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures