MYCL

Summary

MYCL (MYCL proto-oncogene, bHLH transcription factor, HGNC:7555) is a protein-coding gene on chromosome 1p34.2, encoding Protein L-Myc (P12524). In precision oncology, MYCL EXPRESSION confers sensitivity to I-BET151 + JQ1 in Multiple Myeloma (CIViC Level D).

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within regulation of inner ear auditory receptor cell differentiation. Located in chromosome and nucleoplasm.

Source: NCBI Gene 4610 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 47 total
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_001033081

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7555
Approved symbol	MYCL
Name	MYCL proto-oncogene, bHLH transcription factor
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	LMYC, bHLHe38
Ensembl gene	ENSG00000116990
Ensembl biotype	protein_coding
OMIM	164850
Entrez	4610

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000372815, ENST00000372816, ENST00000397332, ENST00000450953

RefSeq mRNA: 3 — MANE Select: NM_001033081 NM_001033081, NM_001033082, NM_005376

CCDS: CCDS30682, CCDS44117, CCDS53300

Canonical transcript exons

ENST00000372816 — 2 exons

Exon	Start	End
ENSE00001458727	39900939	39901917
ENSE00001936518	39895428	39897970

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 90.19.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4829 / max 454.5918, expressed in 899 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11888	2.6892	752
11889	1.3620	447
11890	0.3885	218
11887	0.0432	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	90.19	gold quality
mononuclear cell	CL:0000842	90.00	gold quality
leukocyte	CL:0000738	89.92	gold quality
skin of leg	UBERON:0001511	88.56	gold quality
epithelium of esophagus	UBERON:0001976	88.38	gold quality
skin of abdomen	UBERON:0001416	88.27	gold quality
esophagus squamous epithelium	UBERON:0006920	88.10	gold quality
upper leg skin	UBERON:0004262	87.58	gold quality
zone of skin	UBERON:0000014	87.32	gold quality
granulocyte	CL:0000094	85.87	gold quality
body of pancreas	UBERON:0001150	85.79	gold quality
mucosa of urinary bladder	UBERON:0001259	85.60	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.00	gold quality
esophagus mucosa	UBERON:0002469	83.93	gold quality
gingiva	UBERON:0001828	83.61	gold quality
gingival epithelium	UBERON:0001949	82.77	gold quality
upper arm skin	UBERON:0004263	82.15	silver quality
lower esophagus mucosa	UBERON:0035834	81.25	gold quality
squamous epithelium	UBERON:0006914	81.07	gold quality
cortical plate	UBERON:0005343	80.84	gold quality
skin of hip	UBERON:0001554	80.34	gold quality
ganglionic eminence	UBERON:0004023	79.91	gold quality
urinary bladder	UBERON:0001255	79.70	gold quality
nasal cavity epithelium	UBERON:0005384	78.87	gold quality
ileal mucosa	UBERON:0000331	78.38	gold quality
pancreas	UBERON:0001264	78.35	gold quality
oral cavity	UBERON:0000167	77.73	gold quality
epithelium of bronchus	UBERON:0002031	77.13	gold quality
mucosa of transverse colon	UBERON:0004991	76.83	gold quality
bronchial epithelial cell	CL:0002328	76.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
KCNQ4	Repression
RLF

Upstream regulators (CollecTRI, top): E2F4, GLI1, MYC, MYF5, MYOD1

miRNA regulators (miRDB)

81 targeting MYCL, 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-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136

Literature-anchored findings (GeneRIF, showing 19)

• L-myc polymorphism may affect the induction of lung cancer by smoking (PMID:11802801)
• L-myc proto oncogene RFLP is associated with lung adenocarcinoma (PMID:11836605)
• Allelic deletions of L-myc in urine from bladder cancer patients (PMID:11956626)
• MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmoary fibrosis (PMID:12169206)
• Colorectal tumor patients whose tumors exhibited loss of heterozygosity at MYCL1 at chromosome 1p34 were likely to have a poor prognosis. (PMID:15014029)
• polymorphisms in the MYCL1 LD region affect lung cancer survival but that the functional element(s) may show population-specific patterns (PMID:17145094)
• L-myc gene polymorphism may have a role in risk of thyroid cancer (PMID:18566574)
• The L-myc gene polymorphism may help detect and prevent HNNMSC and LLC in susceptible individuals. It may also contribute to estimation of tumor behavior in patients with HNNMSC. (PMID:18645122)
• L-Myc may have a role in Merkel cell carcinoma pathogenesis (PMID:19020549)
• The results demonstrate that MYCL1 rs3134613 is associated with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer. (PMID:20874233)
• MYCL1 is the target of hsa-miR-1827. A rs3134615 G>T SNP in the 3’-UTR altered regulation of MYCL1 expression. This SNP was associated with increased susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827. (PMID:21676885)
• The polymorphism of H-ras and L-myc genes is not related to colorectal cancer risk, but there is a synergy between H-ras and L-myc polymorphisms in the development of rectal cancer. (PMID:22490849)
• Several tagging SNPs and haplotypes in TRIT1, MYCL1 and MFSD2A region are significantly associated with risk and clinicopathological features of gastric cancer in a Chinese population. (PMID:23349019)
• These results suggest that Mycl1 expression might be useful as a biomarker to predict prognosis and is a promising therapeutic target for patients with gastric cancer. (PMID:25528583)
• display of the influence of MYCL1 gene on invasion and migration phenotype of gastric cancer cells and a possible explanation from the aspect of structural alteration; results suggested that downregulation of MYCL1 may be a potential therapeutic strategy for gastric cancer (PMID:31025404)
• MYCL1 Amplification and Expression of L-Myc and c-Myc in Surgically Resected Small-Cell Lung Carcinoma. (PMID:34257619)
• MYCL promotes iPSC-like colony formation via MYC Box 0 and 2 domains. (PMID:34930932)
• MYCL promotes the progression of triplenegative breast cancer by activating the JAK/STAT3 pathway. (PMID:36177900)
• Comparative study on the mutation spectrum of L-MYC and C-MYC genes of blood cfDNA in patients with ovarian cancer and healthy females. (PMID:37827180)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mycla	ENSDARG00000006003
danio_rerio	myclb	ENSDARG00000034956
mus_musculus	Mycl	ENSMUSG00000028654
rattus_norvegicus	Mycl	ENSRNOG00000014259

Paralogs (2): MYCN (ENSG00000134323), MYC (ENSG00000136997)

Protein

Protein identifiers

Protein L-Myc — P12524 (reviewed: P12524)

Alternative names: Class E basic helix-loop-helix protein 38, Protein L-Myc-1, V-myc myelocytomatosis viral oncogene homolog

All UniProt accessions (2): E9PQS5, P12524

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX.

Subcellular location. Nucleus.

Isoforms (3)

UniProt ID	Names	Canonical?
P12524-1	1	yes
P12524-2	2, Short
P12524-3	3

RefSeq proteins (3): NP_001028253, NP_001028254, NP_005367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002418	Tscrpt_reg_Myc	Family
IPR011598	bHLH_dom	Domain
IPR012682	Tscrpt_reg_Myc_N	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050433	Myc_transcription_factors	Family

Pfam: PF00010, PF01056

UniProt features (11 total): region of interest 4, splice variant 3, chain 1, domain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12524-F1	64.82	0.24

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 283 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GGTGTGT_MIR329, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_NEUROGENESIS, CTATGCA_MIR153, USF_C, GCM_MYCL1, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_UP, KRASNOSELSKAYA_ILF3_TARGETS_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, TCF4_Q5, RICKMAN_METASTASIS_DN, GOBP_EAR_DEVELOPMENT

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), regulation of inner ear auditory receptor cell differentiation (GO:0045607), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), protein dimerization activity (GO:0046983), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
inner ear auditory receptor cell differentiation	1
regulation of epidermal cell differentiation	1
regulation of inner ear receptor cell differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
protein binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYCL	MAX	P25912	851
MYCL	EP400	Q96L91	829
MYCL	RLF	Q13129	804
MYCL	LIN28A	Q9H9Z2	763
MYCL	PPIE	Q9UNP9	729
MYCL	KLF4	P78338	714
MYCL	SOX2	P48431	696
MYCL	GLIS1	Q8NBF1	678
MYCL	TP53	P04637	635
MYCL	POU5F1	P31359	618
MYCL	COL9A2	Q14055	604
MYCL	REEP5	Q00765	580
MYCL	WDR12	Q9GZL7	573
MYCL	MNT	Q99583	549
MYCL	NANOG	Q9H9S0	547

IntAct

20 interactions, top by confidence:

A	B	Type	Score
MAX	E2F6	psi-mi:“MI:0914”(association)	0.710
MYCL	CASK	psi-mi:“MI:0914”(association)	0.350
MYCL	KIF5C	psi-mi:“MI:0914”(association)	0.350
AKT1	MYCL	psi-mi:“MI:2364”(proximity)	0.270
BRAF	MYCL	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	MYCL	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	MYCL	psi-mi:“MI:2364”(proximity)	0.270
MYCL	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	MYCL	psi-mi:“MI:2364”(proximity)	0.270
MYCL	SPOP	psi-mi:“MI:2364”(proximity)	0.270
SPOP	MYCL	psi-mi:“MI:2364”(proximity)	0.270
PTPN11	MYCL	psi-mi:“MI:2364”(proximity)	0.270
MYCL	PTEN	psi-mi:“MI:2364”(proximity)	0.270
MYCL	EGFR	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (87): KLC3 (Affinity Capture-MS), KLC4 (Affinity Capture-MS), KAT5 (Affinity Capture-MS), EPC1 (Affinity Capture-MS), ING3 (Affinity Capture-MS), EPC2 (Affinity Capture-MS), EP400 (Affinity Capture-MS), KIF5A (Affinity Capture-MS), TRRAP (Affinity Capture-MS), KLC2 (Affinity Capture-MS), MBTD1 (Affinity Capture-MS), VPS72 (Affinity Capture-MS), MEAF6 (Affinity Capture-MS), JAZF1 (Affinity Capture-MS), KIF5B (Affinity Capture-MS)

ESM2 similar proteins: A2RU30, D3YN49, D3ZDX9, D6RGH6, E9PV82, F1QN48, F1SLM8, F7BHS0, G3N1S4, H2M146, O35451, O94983, P10166, P12524, P12525, P20389, P23999, Q08B36, Q14140, Q14153, Q1HGE8, Q3UZ45, Q5JXC2, Q5M9G5, Q5R815, Q61817, Q64210, Q68DK7, Q6NSI3, Q6P1D7, Q6PB51, Q6PDM1, Q7TNY7, Q80Y50, Q8BP99, Q8BXQ8, Q8IY92, Q8K3I4, Q8K589, Q8R0W1

Diamond homologs: A1YG22, A2T7L5, B8XIA5, P01106, P01108, P01109, P01110, P03966, P04198, P06171, P06295, P06646, P09416, P0C0N8, P0C0N9, P10166, P10395, P12523, P12524, P15063, P15171, P18444, P20389, P21438, P22555, P23583, P23999, P24793, P26014, P28574, P49032, P49033, P49709, P52160, P52161, P52162, P52164, P61244, P61245, P68271

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MYCL	up-regulates	Proliferation
MYCL	up-regulates	Differentiation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

302 predictions. Top by Δscore:

Variant	Effect	Δscore
1:39897967:TTCT:T	acceptor_gain	1.0000
1:39897969:CT:C	acceptor_gain	1.0000
1:39897971:C:CC	acceptor_gain	1.0000
1:39897976:C:CT	acceptor_gain	1.0000
1:39897976:C:T	acceptor_gain	1.0000
1:39897977:G:T	acceptor_gain	1.0000
1:39897989:C:CT	acceptor_gain	1.0000
1:39897990:A:T	acceptor_gain	1.0000
1:39897966:ATTCT:A	acceptor_gain	0.9900
1:39897970:TC:T	acceptor_loss	0.9900
1:39897971:C:CA	acceptor_loss	0.9900
1:39897972:T:C	acceptor_loss	0.9900
1:39900933:CCTTA:C	donor_loss	0.9900
1:39900934:CTTA:C	donor_loss	0.9900
1:39900935:TTACC:T	donor_loss	0.9900
1:39900936:TACCC:T	donor_loss	0.9900
1:39900937:A:AC	donor_gain	0.9900
1:39900937:A:C	donor_loss	0.9900
1:39900937:AC:A	donor_gain	0.9900
1:39900938:C:CC	donor_gain	0.9900
1:39900938:CC:C	donor_gain	0.9900
1:39897967:TTCTC:T	acceptor_gain	0.9800
1:39897968:TCTC:T	acceptor_gain	0.9800
1:39897969:CTCT:C	acceptor_gain	0.9800
1:39901803:CTCAC:C	donor_loss	0.9700
1:39901804:TCACC:T	donor_loss	0.9700
1:39901344:T:TA	donor_gain	0.9600
1:39901440:CTCC:C	acceptor_gain	0.9600
1:39901825:C:CT	donor_gain	0.9500
1:39901441:TCCC:T	acceptor_loss	0.9400

AlphaMissense

2371 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:39897499:A:G	L323P	1.000
1:39897510:T:A	K319N	1.000
1:39897510:T:G	K319N	1.000
1:39897556:A:G	L304P	1.000
1:39897565:A:G	F301S	1.000
1:39897577:A:G	L297P	1.000
1:39897586:C:G	R294P	1.000
1:39897588:C:A	R293S	1.000
1:39897588:C:G	R293S	1.000
1:39897589:C:A	R293M	1.000
1:39897589:C:G	R293T	1.000
1:39897595:C:G	R291P	1.000
1:39897596:G:T	R291S	1.000
1:39897597:C:A	E290D	1.000
1:39897597:C:G	E290D	1.000
1:39897598:T:A	E290V	1.000
1:39897599:C:T	E290K	1.000
1:39897611:G:C	H286D	1.000
1:39901336:G:C	F33L	1.000
1:39901336:G:T	F33L	1.000
1:39901338:A:G	F33L	1.000
1:39901347:A:G	W30R	1.000
1:39901347:A:T	W30R	1.000
1:39897490:G:T	A326D	0.999
1:39897491:C:G	A326P	0.999
1:39897499:A:T	L323Q	0.999
1:39897502:A:T	I322N	0.999
1:39897511:T:A	K319I	0.999
1:39897512:T:C	K319E	0.999
1:39897552:C:A	R305S	0.999

dbSNP variants (sampled 300 via entrez): RS1000383217 (1:39900118 T>C), RS1000703940 (1:39898441 A>G), RS1001412518 (1:39899831 T>C), RS1001763850 (1:39899081 A>C,G), RS1002173108 (1:39901270 G>C), RS1002780086 (1:39899689 G>A), RS1002931163 (1:39899364 G>A), RS1003359409 (1:39903910 T>A), RS1003519625 (1:39897923 C>A,T), RS1004024765 (1:39899048 G>A), RS1004140693 (1:39898784 A>G), RS1004187969 (1:39898260 T>C), RS1004200986 (1:39895050 C>A,G), RS1005055787 (1:39902493 G>A), RS1005129214 (1:39902307 A>G,T)

Disease associations

OMIM: gene MIM:164850 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_380	Refractive error	4.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
MYCL EXPRESSION	I-BET151 + JQ1	Multiple Myeloma	Sensitivity/Response	CIViC D	EID1706

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, affects cotreatment	5
trichostatin A	affects cotreatment, decreases expression, affects expression, increases expression	4
sodium arsenite	decreases expression, increases expression	4
mercuric bromide	decreases expression, affects cotreatment	2
Air Pollutants	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Calcitriol	increases expression, affects cotreatment	2
Estradiol	decreases expression, affects cotreatment	2
Lipopolysaccharides	increases expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Testosterone	affects cotreatment, increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	decreases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
seocalcitol	increases expression	1
monomethylarsonous 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	decreases expression, affects cotreatment	1
licochalcone B	increases expression	1
GSK1210151A	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Endosulfan	increases expression	1
Formaldehyde	decreases expression	1
Methotrexate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 somatic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_LJ42	LM-NSC008	Somatic stem cell	Female

Clinical trials (associated diseases)

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