CARMIL2

protein-coding

capping protein regulator and myosin 1 linker 2

Gene summary

This gene encodes a member of the CARMIL (capping protein, Arp2/3, myosin-I linker) family of proteins. The encoded protein interacts with and negatively regulates the heterodimeric capping protein and promotes cell migration. Reduced expression of this gene has been observed in human psoriasis patients. Mutations in this gene cause a human immunodeficiency syndrome characterized by smooth muscle tumors and impaired T-cell function. [provided by RefSeq, May 2017]

Previous symbols:

RLTPR

MANE transcript

NM_001013838.3

Inheritance

ClinVar variants

P:86U:462B:376

Top phenotype

Immunodeficiency 58

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr16:67,644,988-67,657,569

External References & Databases

Ensembl (ENSG00000159753)

Transcript & Mutation Effects

hg38 • Region Span ~12.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe combined immunodeficiency due to CARMIL2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029134

Submitter: Labcorp Genetics (formerly Invitae)

severe combined immunodeficiency due to CARMIL2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0029134

Submitter: ClinGen

*CARMIL2 *(i.e., *RLTPR*) was first reported in relation to autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency in 2016 (Sorte HS et al., PMID: 27896283). Severe combined immunodeficiency due to CARMIL2 deficiency is a combined immunodeficiency with prominent immune dysregulation. This is a heterogeneous disorder characterized by failure to thrive, recurrent upper and lower respiratory infections, skin abnormalities (note the occurrence of these require infection and/or immune-mediated processes in addition to CARMIL2 defects), eczema, warts, seborrheic dermatitis, allergies, and asthma. Additional features of disease often observed include candidiasis, herpes infection, *Molloscum contagiosum* infection, early-onset inflammatory bowel disease, chronic diarrhea, and Epstein Barr virus-related smooth muscle tumors. Immunologically, these patients typically display impaired naïve T-cell activation, differentiation, proliferation, and effector function, and defective T-cell memory responses. More than 50 individuals with autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency have been reported to date (PMID: 34287962). Six variants (missense and frameshift) that have been reported in 7 probands in 3 publications (PMIDs: 27896283, 34287962, 36727012) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 23793062, 27647348, 27647349, 28112205). *CARMIL2* has been shown to be expressed in immune organs and T cells (PMID: 23793062, 27647349), function in CD28 signaling, and facilitate scaffold interactions with CD28 and CARD11 downstream of T-cell receptor stimulation (PMID: 27647348, 28112205). Two different mouse models demonstrate T-cell abnormalities when CARMIL2 is either deleted or mutated to impair function (PMID: 23793062, 27647348). T-cell abnormalities in cytokine production, proliferation, and migration have been observed in cells derived from many different patients (PMID: 27647349, 28112205). In summary, there is definitive evidence supporting the relationship between *CARMIL2* and autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

severe combined immunodeficiency due to CARMIL2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029134

Submitter: G2P

severe combined immunodeficiency due to CARMIL2 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0029134

Submitter: Orphanet

severe combined immunodeficiency due to CARMIL2 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0029134

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Immunodeficiency 58AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Oncologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Individuals may have severe and frequent infections, and prophylactic measures, as well as early and aggressive treatment of infections may be beneficial; Individuals may be at increased risk of certain types of neoplasms, and awareness may allow prompt diagnosis and management

Refs: 27647349; 27896283; 28112205; 29479355

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CARMIL2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 1206

not specifiedTotal: 123

Severe combined immunodeficiency due to CARMIL2 deficiencyTotal: 44

CARMIL2-related disorderTotal: 42

Inborn genetic diseasesTotal: 16

Combined immunodeficiencyTotal: 3

RLTPR -related disordersTotal: 1

Autosomal recessive congenital ichthyosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001013838.3. 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			7 clinvar	343 clinvar	5 clinvar	355
missense	1 clinvar	5 clinvar	446 clinvar	23 clinvar	5 clinvar	480
nonsense	16 clinvar	4 clinvar	2 clinvar			22
start loss						0
frameshift	32 clinvar	8 clinvar	1 clinvar			41
splice donor/acceptor (+/-2bp)	2 clinvar	18 clinvar	6 clinvar			26
Total	51	35	462	366	10	924

Highest pathogenic variant AF is 0.0000487285

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001013838.3	RefSeq	NP_001013860.1	38	MANE Select
ENST00000334583.11	Ensembl	ENSP00000334958.5	38	MANE Select
NM_001317026.3	RefSeq	NP_001303955.1	38	Standard
NM_001438244.1	RefSeq	NP_001425173.1	39	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

establishment or maintenance of cell polarity
positive regulation of lamellipodium assembly
maintenance of cell polarity
positive regulation of cell migration
wound healing, spreading of cells

Molecular Function

phospholipid binding
protein-containing complex binding

Cellular Component

ruffle
cytoplasm
plasma membrane
actin cytoskeleton
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334583
Coding exons: 38
Length: 12651
Individuals with no LoFs: 124971
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125027
p: 0.000224

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.57	703	831	0.846	0.0000522	9032
Missense (PolyPhen)		179	236.34	0.7574		2931
Synonymous	0.774	346	365	0.948	0.0000242	3095
Loss of Function	4.81	32	77.8	0.411	0.00000445	803

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00051	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00029	0.00027	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00029	0.00026	rare
South Asian	0.00024	0.00023	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization (PubMed:26466680). Plays a role in cell protrusion formations; involved in cell polarity, lamellipodial assembly, membrane ruffling and macropinosome formations (PubMed:19846667, PubMed:26578515, PubMed:26466680). Involved as well in cell migration and invadopodia formation during wound healing (PubMed:19846667, PubMed:26578515, PubMed:26466680). {ECO:0000269|PubMed:19846667, ECO:0000269|PubMed:26466680, ECO:0000269|PubMed:26578515}.;

Recessive Scores

pRec: 0.0922

Intolerance Scores

RVIS EVS: -1.12
RVIS percentile EVS: 6.61

Essentials

Essential (gene trap): N