Hypomagnesemia, seizures, and intellectual disability 1

Summary

Hypomagnesemia, seizures, and intellectual disability 1 (MONDO:0020787) is a disease caused by CNNM2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CNNM2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 111

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomagnesemia, seizures, and intellectual disability 1
Mondo ID	MONDO:0020787
OMIM	616418
UMLS	C4225333
MedGen	906582
GARD	0025248
Is cancer (heuristic)	no

Also known as: HOMGSMR1 · hypomagnesemia, seizures, and mental retardation

Data availability: 111 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial primary hypomagnesemia › familial primary hypomagnesemia with normocalcuria › familial primary hypomagnesemia with normocalciuria and normocalcemia › hypomagnesemia, seizures, and intellectual disability › hypomagnesemia, seizures, and intellectual disability 1

Related subtypes (1): hypomagnesemia, seizures, and intellectual disability 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

111 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 12 likely pathogenic, 11 pathogenic, 7 likely benign, 7 benign/likely benign, 4 conflicting classifications of pathogenicity, 3 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
192323	NM_017649.5(CNNM2):c.364G>A (p.Glu122Lys)	CNNM2	Pathogenic	criteria provided, single submitter
192324	NM_017649.5(CNNM2):c.1069G>A (p.Glu357Lys)	CNNM2	Pathogenic	criteria provided, single submitter
192325	NM_017649.5(CNNM2):c.806C>G (p.Ser269Trp)	CNNM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2578368	NM_017649.5(CNNM2):c.274G>C (p.Ala92Pro)	CNNM2	Pathogenic	criteria provided, single submitter
2578372	NM_017649.5(CNNM2):c.970G>C (p.Val324Leu)	CNNM2	Pathogenic	criteria provided, single submitter
996041	NM_017649.5(CNNM2):c.143T>C (p.Leu48Pro)	CNNM2	Pathogenic	no assertion criteria provided
996042	NM_017649.5(CNNM2):c.942C>G (p.Tyr314Ter)	CNNM2	Pathogenic	no assertion criteria provided
996043	NM_017649.5(CNNM2):c.955CTG[2] (p.Leu321del)	CNNM2	Pathogenic	no assertion criteria provided
996044	NM_017649.5(CNNM2):c.970G>A (p.Val324Met)	CNNM2	Pathogenic	no assertion criteria provided
996045	NM_017649.5(CNNM2):c.1253T>C (p.Leu418Pro)	CNNM2	Pathogenic	no assertion criteria provided
996052	NC_000010.10:g.(?104678237)(104816721_?)del	CNNM2	Pathogenic	no assertion criteria provided
996053	NM_017649.5(CNNM2):c.1842_1844del (p.Ser614_Glu615delinsArg)	CNNM2	Pathogenic	no assertion criteria provided
1098410	NM_017649.5(CNNM2):c.1804C>T (p.Arg602Ter)	CNNM2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342906	NM_017649.5(CNNM2):c.312_315dup (p.Tyr106fs)	CNNM2	Likely pathogenic	criteria provided, single submitter
1696568	NM_017649.5(CNNM2):c.522dup (p.Ile175fs)	CNNM2	Likely pathogenic	criteria provided, single submitter
1709797	NM_017649.5(CNNM2):c.992C>T (p.Thr331Ile)	CNNM2	Likely pathogenic	criteria provided, single submitter
3376914	NM_017649.5(CNNM2):c.1067G>A (p.Gly356Glu)	CNNM2	Likely pathogenic	criteria provided, single submitter
3590449	NM_017649.5(CNNM2):c.1764C>G (p.Tyr588Ter)	CNNM2	Likely pathogenic	criteria provided, single submitter
3590455	NM_017649.5(CNNM2):c.1862C>A (p.Ser621Ter)	CNNM2	Likely pathogenic	criteria provided, single submitter
4072324	NM_017649.5(CNNM2):c.1207C>T (p.Gln403Ter)	CNNM2	Likely pathogenic	criteria provided, single submitter
4074742	NM_017649.5(CNNM2):c.52_55dup (p.Ala19fs)	CNNM2	Likely pathogenic	criteria provided, single submitter
4755466	Single allele	CNNM2	Likely pathogenic	criteria provided, single submitter
4819658	NM_017649.5(CNNM2):c.1300ATC[1] (p.Ile435del)	CNNM2	Likely pathogenic	criteria provided, single submitter
996055	NM_017649.5(CNNM2):c.2389C>T (p.Arg797Ter)	CNNM2	Likely pathogenic	criteria provided, single submitter
1487188	NM_017649.5(CNNM2):c.237G>A (p.Leu79=)	CNNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2194751	NM_017649.5(CNNM2):c.433A>G (p.Ser145Gly)	CNNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802633	NM_017649.5(CNNM2):c.2240A>G (p.Asn747Ser)	CNNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
996054	NM_017649.5(CNNM2):c.2384C>T (p.Ser795Leu)	CNNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1375331	NM_017649.5(CNNM2):c.118A>G (p.Ile40Val)	CNNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1395222	NM_017649.5(CNNM2):c.1528C>T (p.Pro510Ser)	CNNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CNNM2	Definitive	Semidominant	hypomagnesemia, seizures, and intellectual disability 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
right adrenal gland	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CNNM2	1,230

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNNM2	Q9H8M5	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
magnesium ion homeostasis	1	1872.4×	5e-04	CNNM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CNNM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CNNM2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CNNM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.