MAGED2

protein-coding

MAGE family member D2, the group of MAGE family|Small nucleolar RNA protein coding host genes

Gene summary

This gene is a member of the MAGED gene family. The MAGED genes are clustered on chromosome Xp11. This gene is located in Xp11.2, a hot spot for X-linked intellectual disability (XLID). Mutations in this gene cause a form of transient antenatal Bartter's syndrome. This gene may also be involved in several types of cancer, including breast cancer and melanoma. The protein encoded by this gene is progressively recruited from the cytoplasm to the nucleoplasm during the interphase and after nucleolar stress and is thus thought to play a role in cell cycle regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

MANE transcript

NM_177433.3

Inheritance

ClinVar variants

P:21U:145B:51

Top phenotype

Bartter syndrome type 5, antenatal transient

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chrX:54,807,599-54,816,015

External References & Databases

Ensembl (ENSG00000102316)

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bartter disease type 5DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010503

Submitter: ClinGen

The MAGED2 gene is located on the X chromosome at p11.21 and encodes melanoma antigen, family D, 2. MAGED2 regulates the expression, localization to the plasma membrane, and function of the sodium chloride cotransporters SLC12A1 (NKCC2) and SLC12A3 (NCC), both of which are critical components of renal salt reabsorption. MAGED2 was first reported in relation to X-linked recessive transient antenatal Bartter syndrome, type 5 in 2016 (Laghmani et al., PMID:27120771). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, transient antenatal Bartter syndrome, type 5 (OMIM:300971) and developmental delay (PMIDs: 27435318, 33504798). 22 variants (missense, in-frame indel, nonsense, frameshift, and large deletion) that have been reported in 26 probands in 4 publications (PMIDs: 27120771, 29146702, 29893154, 31302915) 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 LOF. This gene-disease association is also supported by experimental evidence (expression studies and in vitro functional assays) (PMID: 27120771). MAGED2 was shown to be expressed in the thick ascending limb of the loop of Henle and in the distal tubules. Furthermore, MAGED2 promotes NKCC2 and NCC expression and activity. Finally, both p.Tyr346Ter and p.Arg446Cys were shown to functionally alter MAGED2 in patient cells and in vitro respectively. In summary, MAGED2 is definitively associated with X-linked recessive transient antenatal Bartter syndrome, type 5. This 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 Tubulopathy GCEP on the meeting date March 17, 2022 (SOP Version 8).

Bartter disease type 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010503

Submitter: Labcorp Genetics (formerly Invitae)

Bartter disease type 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010503

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bartter syndrome type 5, antenatal transientXL

Manifestation: Renal

Intervention: Renal

Rationale: The condition can involve prenatal and postnatal manifestations, and awareness may allow medical management of electrolyte abnormalities during the transient period when children are affected

Refs: 27120771

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAGED2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 110

Inborn genetic diseasesTotal: 44

Bartter disease type 5Total: 20

not specifiedTotal: 13

MAGED2-related disorderTotal: 10

Hypoplasia of the corpus callosumTotal: 1

HypotoniaTotal: 1

Renal tubulopathiesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177433.3. 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			9 clinvar	27 clinvar	10 clinvar	46
missense		1 clinvar	97 clinvar	11 clinvar	3 clinvar	112
nonsense	6 clinvar	5 clinvar	6 clinvar			17
start loss			1 clinvar			1
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	30 clinvar			36
Total	10	11	145	38	13	217

Highest pathogenic variant AF is 9.733393e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 123 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_177433.3	RefSeq	NP_803182.1	11	MANE Select
ENST00000375068.6	Ensembl	ENSP00000364209.1	11	MANE Select
NM_014599.6	RefSeq	NP_055414.2	11	Standard
NM_201222.3	RefSeq	NP_957516.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet degranulation
Response to elevated platelet cytosolic Ca2+
Platelet activation, signaling and aggregation
Hemostasis

Biological Process

platelet degranulation
female pregnancy
renal sodium ion absorption

Molecular Function

protein binding

Cellular Component

extracellular region
nucleus
nucleolus
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375068
Coding exons: 11
Length: 8414
Individuals with no LoFs: 125280
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125281
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.34	128	227	0.563	0.0000179	3892
Missense (PolyPhen)		33	71.623	0.46074		1336
Synonymous	0.538	77	83.2	0.925	0.00000643	1223
Loss of Function	3.97	1	20.3	0.0492	0.00000168	343

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000063	0.000047	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule. {ECO:0000269|PubMed:27120771}.;

Recessive Scores

pRec: 0.121

Intolerance Scores

RVIS EVS: -0.23
RVIS percentile EVS: 37.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.788

Gene Damage Prediction

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