CNNM2

Chr 10ADAR

cyclin and CBS domain divalent metal cation transport mediator 2

Also known as: ACDP2, HOMG6, HOMGSMR, SLC70A2

NCBI Gene: 54805 ENSG00000148842 UniProt: Q9H8M5 OMIM: 607803

CNNM2 encodes a divalent metal cation transporter that mediates epithelial transport and renal reabsorption of magnesium. Mutations cause hypomagnesemia with either isolated renal involvement or a more severe phenotype with seizures and intellectual disability, inherited in either autosomal dominant or recessive patterns. The gene is highly constrained against loss-of-function variants (pLI 0.995, LOEUF 0.267), indicating intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.272 OMIM phenotypes

Clinical Summary— CNNM2

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Gene-Disease Validity (ClinGen)

hypomagnesemia, seizures, and intellectual disability 1 · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

44 unique Pathogenic / Likely Pathogenic· 278 VUS of 542 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.27LOEUF

pLI 0.995

Z-score 4.48

OE 0.10 (0.05–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.41Z-score

OE missense 0.44 (0.40–0.49)

219 obs / 495.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.27)

0≤0.351.4

Missense OE?0.44 (0.40–0.49)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 29.0Missense obs/exp: 219 / 495.2Syn Z: -1.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCNNM2-related neurodevelopmental disorder with hypomagnesemiaLOFAR

strongCNNM2-related neurodevelopmental disorder with hypomagnesemiaOTHERAD

This gene — mechanism propensity

0.4686th %ile

GOF

0.6248th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 43% of P/LP variants are LoF · LOEUF 0.27

Literature Evidence

LOFThe phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33600043 ↗

ClinVar Variant Classifications

542 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic20

VUS278

Likely Benign155

Benign41

Conflicting14

Pathogenic

Likely Pathogenic

278

VUS

155

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	13	2	0	24
Likely Pathogenic	10	9	1	0	20
VUS	8	241	21	8	278
Likely Benign	0	5	32	118	155
Benign	0	2	30	9	41
Conflicting	—				14
Total	27	270	86	135	532

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap CNNM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →