LCP2

protein-coding

lymphocyte cytosolic protein 2, the group of SH2 domain containing

Gene summary

This gene encodes an adapter protein that acts as a substrate of the T cell antigen receptor (TCR)-activated protein tyrosine kinase pathway. The encoded protein associates with growth factor receptor bound protein 2, and is thought to play a role TCR-mediated intracellular signal transduction. A similar protein in mouse plays a role in normal T-cell development and activation. Mice lacking this gene show subcutaneous and intraperitoneal fetal hemorrhaging, dysfunctional platelets and impaired viability. [provided by RefSeq, Nov 2016]

Previous symbols:

SLP76

MANE transcript

NM_005565.5

Inheritance

ClinVar variants

P:1U:76B:13

Top phenotype

Immunodeficiency 81

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr5:170,246,233-170,297,815

External References & Databases

Ensembl (ENSG00000043462)

Transcript & Mutation Effects

hg38 • Region Span ~51.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 81LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030302

Submitter: Ambry Genetics

immunodeficiency 81LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030302

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 81DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030302

Submitter: ClinGen

Biallelic germline variants in LCP2 (SLP76) were first reported in relation to combined T and B cell immunodeficiency in 2020 (PMID: 33231617). Patients with *LCP2*-related combined immunodeficiency demonstrate recurrent fungal infections with T cell dysfunction and associations with EBV-related infection and lymphoproliferation, platelet dysfunction and neutrophil dysfunction. Four variants were identified in the literature and are composed of missense, splice site and frameshift mutations (PMID: 33231617,36474126, 37211057). Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have not been reported to have a clinical phenotype. *LCP2* encodes for the protein SLP76, an important intermediate of T cell receptor signaling. Following T cell activation, SLP76 is recruited to membrane bound phosphorylated LAT by Gads and mediates the phosphorylation of ITK, resulting in the phosphorylation and PLC-gamma1. Activation of PLC-gamma1 is required for the initiation of the NFAT and MAPK signaling pathways, both of which are required for the generation of functional T cell signaling. A combination of cell lines and animal models have helped to identify the role SLP76 plays in the immune system. Studies in cell lines have identified interacting partners of SLP76, as well as important domains of the protein required for supporting T cell receptor signaling (PMID:7706237, 17420479, 10556826, 9665884, 16354835, 9257823). Mouse models of total SLP76 deficiency replicate peripheral T cell deficiency and platelet defect identified in patients (PMID: 9695951, 9884330). In these models, SLP76 deficient cells demonstrate a developmental block during double negative thymocyte development, leading to an absence of peripheral T cells (PMID: 9695951). Mouse models studying the impact of individual domains of SLP76 have shown different severity of thymocyte development block and resulting peripheral T cell survival, suggesting genotype-phenotype correlations (PMID: 11792851). This may be evident in the identified patients, as the age and presenting symptoms of the patients are varied. In summary, there is definitive evidence to support this gene-disease relationship. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on 2/15/2024 (SOP Version 9).

immunodeficiency 81STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030302

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 81AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious; Hematologic

Rationale: The condition may involve severe, early-onset infections, and preventative measures and early and aggressive treatment of infections may be beneficial; The condition may involve autoimmune hemolytic anemia, and response to steroid treatment has been described; HSCT has been described

Refs: 33231617

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LCP2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 76

not providedTotal: 12

Immunodeficiency 81Total: 4

LCP2-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005565.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	10 clinvar		11
missense			72 clinvar	3 clinvar		75
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		3 clinvar			4
Total	1	0	76	13	0	90

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005565.5	RefSeq	NP_005556.1	21	MANE Select
ENST00000046794.10	Ensembl	ENSP00000046794.5	21	MANE Select
ENST00000520344.1	Ensembl	ENSP00000430391.1	8	Standard
ENST00000521416.5	Ensembl	ENSP00000428871.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Fc epsilon RI signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Natural killer cell mediated cytotoxicity - Homo sapiens (human)

Biological Process

immune response
transmembrane receptor protein tyrosine kinase signaling pathway
platelet activation
intracellular signal transduction
Fc-epsilon receptor signaling pathway

Molecular Function

protein binding

Cellular Component

cytosol
cell-cell junction
TCR signalosome
plasma membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000046794
Coding exons: 21
Length: 51991
Individuals with no LoFs: 124628
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 124638
p: 0.0000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.918	243	287	0.847	0.0000158	3467
Missense (PolyPhen)		49	98.256	0.4987		1153
Synonymous	1.10	96	111	0.867	0.00000676	978
Loss of Function	4.52	6	34.7	0.173	0.00000180	433

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in T-cell antigen receptor mediated signaling.;

Recessive Scores

pRec: 0.287

Intolerance Scores

RVIS EVS: -0.49
RVIS percentile EVS: 22.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.118

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium