LETM2

Summary

LETM2 (leucine zipper and EF-hand containing transmembrane protein 2, HGNC:14648) is a protein-coding gene on chromosome 8p11.23, encoding LETM1 domain-containing protein LETM2, mitochondrial (Q2VYF4).

Predicted to enable transmembrane transporter activity. Predicted to be involved in mitochondrial calcium ion transmembrane transport and mitochondrion organization. Located in mitochondrion.

Source: NCBI Gene 137994 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 72 total
• MANE Select transcript: NM_001286819

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14648
Approved symbol	LETM2
Name	leucine zipper and EF-hand containing transmembrane protein 2
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25409, SLC55A2
Ensembl gene	ENSG00000165046
Ensembl biotype	protein_coding
OMIM	620380
Entrez	137994

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000297720, ENST00000379957, ENST00000518121, ENST00000518883, ENST00000519476, ENST00000523268, ENST00000523983, ENST00000524874, ENST00000526075, ENST00000526356, ENST00000527175, ENST00000527334, ENST00000527710, ENST00000528827, ENST00000530448, ENST00000889546, ENST00000948387

RefSeq mRNA: 9 — MANE Select: NM_001286819 NM_001199659, NM_001199660, NM_001286787, NM_001286819, NM_001286821, NM_001330515, NM_001363204, NM_001363205, NM_144652

CCDS: CCDS56534, CCDS6106, CCDS69466, CCDS75731, CCDS83282

Canonical transcript exons

ENST00000379957 — 11 exons

Exon	Start	End
ENSE00001527473	38394098	38394241
ENSE00001806127	38392542	38392995
ENSE00002122767	38386476	38386568
ENSE00003526354	38400272	38400409
ENSE00003526982	38400853	38401053
ENSE00003528064	38402525	38402644
ENSE00003536187	38407362	38407463
ENSE00003542896	38404393	38404506
ENSE00003589066	38406946	38407038
ENSE00003661105	38387950	38388030
ENSE00003901386	38408212	38409527

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 90.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.7601 / max 249.4772, expressed in 1515 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88490	4.5793	1280
88495	1.5223	414
88497	1.0469	312
88493	0.4509	198
88496	0.2946	112
88494	0.2878	129
88486	0.2632	95
88489	0.1522	53
88488	0.0929	39
88487	0.0484	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	90.16	gold quality
right testis	UBERON:0004534	89.49	gold quality
cerebellar hemisphere	UBERON:0002245	89.26	gold quality
cerebellar cortex	UBERON:0002129	89.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.85	gold quality
testis	UBERON:0000473	87.59	gold quality
cerebellum	UBERON:0002037	86.66	gold quality
secondary oocyte	CL:0000655	80.90	gold quality
islet of Langerhans	UBERON:0000006	78.05	gold quality
descending thoracic aorta	UBERON:0002345	77.30	gold quality
adenohypophysis	UBERON:0002196	76.01	gold quality
stromal cell of endometrium	CL:0002255	75.94	gold quality
cortical plate	UBERON:0005343	75.87	gold quality
oocyte	CL:0000023	75.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.70	gold quality
right coronary artery	UBERON:0001625	75.62	gold quality
left uterine tube	UBERON:0001303	75.61	gold quality
anterior cingulate cortex	UBERON:0009835	75.54	gold quality
leukocyte	CL:0000738	75.41	gold quality
body of pancreas	UBERON:0001150	75.39	gold quality
omental fat pad	UBERON:0010414	75.24	gold quality
right frontal lobe	UBERON:0002810	75.17	gold quality
peritoneum	UBERON:0002358	75.15	gold quality
granulocyte	CL:0000094	75.13	gold quality
pancreas	UBERON:0001264	75.00	gold quality
monocyte	CL:0000576	74.98	gold quality
thoracic aorta	UBERON:0001515	74.77	gold quality
ascending aorta	UBERON:0001496	74.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.39	gold quality
lower esophagus muscularis layer	UBERON:0035833	74.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting LETM2, 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-126-5P	100.00	72.71	3180
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-140-3P	99.04	67.69	1324

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	letm2	ENSDARG00000077515
mus_musculus	Letm2	ENSMUSG00000037363
rattus_norvegicus	Letm2	ENSRNOG00000026180

Paralogs (2): LETMD1 (ENSG00000050426), LETM1 (ENSG00000168924)

Protein

Protein identifiers

LETM1 domain-containing protein LETM2, mitochondrial — Q2VYF4 (reviewed: Q2VYF4)

Alternative names: LETM1 and EF-hand domain-containing protein 2, Leucine zipper-EF-hand-containing transmembrane protein 1-like

All UniProt accessions (8): A8K1M9, E5RJN4, E5RK40, Q2VYF4, E9PIC7, E9PMA4, E9PN52, H0YCZ8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Mitochondrion inner membrane.

Isoforms (4)

UniProt ID	Names	Canonical?
Q2VYF4-1	1	yes
Q2VYF4-2	2
Q2VYF4-3	3
Q2VYF4-4	4

RefSeq proteins (9): NP_001186588, NP_001186589, NP_001273716, NP_001273748, NP_001273750, NP_001317444, NP_001350133, NP_001350134, NP_653253 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033122	LETM1-like_RBD	Domain
IPR044202	LETM1/MDM38-like	Family
IPR045742	LETM2_N	Domain

Pfam: PF07766, PF19324

UniProt features (17 total): splice variant 4, compositionally biased region 3, topological domain 2, region of interest 2, transit peptide 1, chain 1, sequence conflict 1, transmembrane region 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2VYF4-F1	62.77	0.15

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, SHEPARD_BMYB_MORPHOLINO_UP, CREBP1_Q2, GOBP_MONOATOMIC_CATION_TRANSPORT, CREB_Q4, E4F1_Q6, GOCC_MITOCHONDRIAL_ENVELOPE, AACTTT_UNKNOWN, SENESE_HDAC1_TARGETS_UP, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_ORGANELLE_INNER_MEMBRANE, MARSON_BOUND_BY_FOXP3_STIMULATED, YATGNWAAT_OCT_C, GOMF_RIBONUCLEOPROTEIN_COMPLEX_BINDING

GO Biological Process (2): mitochondrial calcium ion transmembrane transport (GO:0006851), mitochondrion organization (GO:0007005)

GO Molecular Function (2): transmembrane transporter activity (GO:0022857), ribosome binding (GO:0043022)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transmembrane transport	1
organelle organization	1
transporter activity	1
transmembrane transport	1
ribonucleoprotein complex binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

947 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LETM2	GOT1L1	Q8NHS2	567
LETM2	NSD3	Q9BZ95	553
LETM2	RAB11FIP1	Q6WKZ4	543
LETM2	BRF2	Q9HAW0	526
LETM2	DDHD2	O94830	522
LETM2	SIRAL2	Q9NWS6	491
LETM2	PLPP5	Q8NEB5	478
LETM2	MICU1	Q9BPX6	462
LETM2	RHBDD3	Q9Y3P4	461
LETM2	BAG4	O95429	448
LETM2	TACC1	O75410	448
LETM2	PLPBP	O94903	448
LETM2	REEP6	Q96HR9	446
LETM2	DNAJC18	Q9H819	427
LETM2	LSM1	O15116	420

IntAct

6 interactions, top by confidence:

A	B	Type	Score
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
LETM2	GAPDHS	psi-mi:“MI:0914”(association)	0.350
LETM1	LETM2	psi-mi:“MI:0914”(association)	0.350
LETM2	EIF3CL	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): LETM2 (Synthetic Lethality), GAPDHS (Affinity Capture-MS), TCTEX1D2 (Affinity Capture-MS), PNMA2 (Affinity Capture-MS), LETM2 (Cross-Linking-MS (XL-MS)), LETM2 (Cross-Linking-MS (XL-MS)), LETM2 (Affinity Capture-MS), AHNAK (Affinity Capture-MS), AK4 (Affinity Capture-MS), AMOT (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), APMAP (Affinity Capture-MS), ARL6IP5 (Affinity Capture-MS), ARPC4 (Affinity Capture-MS), ASAH1 (Affinity Capture-MS)

ESM2 similar proteins: A2VD95, A4UMC5, D6WIX5, E7EXT2, O13920, O95202, P70302, P84903, P91927, P91928, Q06493, Q08CK1, Q0P4W3, Q0VA06, Q0VCA3, Q13586, Q1KKT4, Q1L987, Q1LY46, Q28DA8, Q29RR5, Q2VYF4, Q3ZC62, Q498P2, Q58CP9, Q5FW14, Q5PQQ5, Q5RAS1, Q5RJT2, Q5U2Y6, Q5XIN6, Q5ZK33, Q5ZKM1, Q66JD1, Q6DI35, Q6PFM4, Q7TNU7, Q7ZU80, Q7ZYV9, Q80X82

Diamond homologs: O13920, O95202, P91927, Q06493, Q08179, Q0VA06, Q0VCA3, Q1LY46, Q28DA8, Q2VYF4, Q5PQQ5, Q5XIN6, Q5ZK33, Q7TNU7, Q9Z2I0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1840 predictions. Top by Δscore:

Variant	Effect	Δscore
8:38401051:G:GT	donor_gain	1.0000
8:38401051:GAA:G	donor_gain	1.0000
8:38401054:G:GG	donor_gain	1.0000
8:38402519:TTTCA:T	acceptor_loss	1.0000
8:38402520:TTCA:T	acceptor_loss	1.0000
8:38402522:CA:C	acceptor_loss	1.0000
8:38402523:A:AG	acceptor_gain	1.0000
8:38402523:AG:A	acceptor_loss	1.0000
8:38402524:G:GA	acceptor_gain	1.0000
8:38402524:GAT:G	acceptor_gain	1.0000
8:38402524:GATA:G	acceptor_gain	1.0000
8:38402642:G:GT	donor_gain	1.0000
8:38402642:GAGG:G	donor_loss	1.0000
8:38402645:GCA:G	donor_loss	1.0000
8:38402646:CAA:C	donor_loss	1.0000
8:38404383:C:A	acceptor_gain	1.0000
8:38404391:A:AG	acceptor_gain	1.0000
8:38404391:AGT:A	acceptor_gain	1.0000
8:38404391:AGTG:A	acceptor_gain	1.0000
8:38404392:G:GA	acceptor_gain	1.0000
8:38404392:GT:G	acceptor_gain	1.0000
8:38404392:GTG:G	acceptor_gain	1.0000
8:38404392:GTGG:G	acceptor_gain	1.0000
8:38404392:GTGGC:G	acceptor_gain	1.0000
8:38404502:GGGAG:G	donor_gain	1.0000
8:38404503:GGAG:G	donor_gain	1.0000
8:38404503:GGAGG:G	donor_gain	1.0000
8:38404504:GAG:G	donor_gain	1.0000
8:38404504:GAGG:G	donor_gain	1.0000
8:38404505:AGG:A	donor_loss	1.0000

AlphaMissense

3191 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:38404393:T:A	W369R	0.994
8:38404393:T:C	W369R	0.994
8:38404395:G:C	W369C	0.990
8:38404395:G:T	W369C	0.990
8:38402568:T:C	L343P	0.989
8:38401016:T:C	L316P	0.988
8:38402637:T:C	L366P	0.988
8:38400950:T:C	L294P	0.986
8:38402625:T:C	L362P	0.986
8:38401048:G:C	D327H	0.985
8:38400324:T:C	L233P	0.984
8:38402595:T:C	M352T	0.980
8:38404403:T:C	L372P	0.979
8:38404421:T:A	V378D	0.978
8:38400320:T:C	F232L	0.977
8:38400322:T:A	F232L	0.977
8:38400322:T:G	F232L	0.977
8:38394099:T:C	L168P	0.976
8:38401004:T:C	L312P	0.976
8:38401049:A:T	D327V	0.976
8:38394221:T:C	F209L	0.974
8:38394223:T:A	F209L	0.974
8:38394223:T:G	F209L	0.974
8:38402589:G:C	R350P	0.974
8:38404436:T:C	L383S	0.973
8:38400959:T:C	L297P	0.972
8:38402576:G:C	A346P	0.972
8:38401048:G:T	D327Y	0.971
8:38401049:A:C	D327A	0.971
8:38401028:T:C	L320P	0.970

dbSNP variants (sampled 300 via entrez): RS1000202792 (8:38392005 G>T), RS1000365460 (8:38402697 T>C), RS1000448269 (8:38387358 G>C), RS1000497460 (8:38397607 T>C,G), RS1000592143 (8:38408799 G>A,T), RS1000633807 (8:38402167 G>A,C), RS1000670706 (8:38408714 C>G,T), RS1000871328 (8:38388752 T>G), RS1000891603 (8:38383604 T>A), RS1000944339 (8:38388434 C>G), RS1001117987 (8:38391277 T>C), RS1001143624 (8:38380917 A>G), RS1001224889 (8:38405059 G>C), RS1001277831 (8:38382209 G>A), RS1001305087 (8:38404841 G>A,C)

Disease associations

OMIM: gene MIM:620380 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003469_12	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06
GCST004521_242	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004946_16	Schizophrenia	1.000000e-11
GCST006803_65	Schizophrenia	6.000000e-10
GCST007201_408	Schizophrenia	1.000000e-06
GCST007201_97	Schizophrenia	1.000000e-12
GCST007269_277	Pulse pressure	2.000000e-11
GCST008103_171	Bipolar disorder	7.000000e-06
GCST009600_31	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-09
GCST90000025_329	Appendicular lean mass	1.000000e-21
GCST90002387_394	Immature fraction of reticulocytes	8.000000e-15
GCST90002388_241	Lymphocyte count	8.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0005763	pulse pressure measurement
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC55 Mitochondrial cation/proton exchangers

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Smoke	decreases expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	increases expression	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Quercetin	increases expression	1
Silicon Dioxide	increases expression	1
Theophylline	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	increases expression	1
Aflatoxin B1	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4G1	HCT116-LETM2-KO-c11	Cancer cell line	Male
CVCL_D4G2	HCT116-LETM2-KO-c2	Cancer cell line	Male

Clinical trials (associated diseases)

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