CNNM4

protein-coding

cyclin and CBS domain divalent metal cation transport mediator 4, the group of Cyclin and CBS domain divalent metal cation transport mediators|MicroRNA protein coding host genes

Gene summary

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 a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]

Previous symbols:

ACDP4

MANE transcript

NM_020184.4

Inheritance

ClinVar variants

P:55U:269B:178

Top phenotype

Jalili syndrome

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr2:96,760,902-96,811,874

External References & Databases

Ensembl (ENSG00000158158)

Transcript & Mutation Effects

hg38 • Region Span ~51.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Jalili syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009007

Submitter: Labcorp Genetics (formerly Invitae)

Jalili syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009007

Submitter: G2P

Jalili syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009007

Submitter: Ambry Genetics

Jalili syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009007

Submitter: Orphanet

Jalili syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009007

Submitter: ClinGen

CNNM4 was first reported in relation to autosomal recessive Jalili syndrome which causes cone rod dystrophy and amelogenesis imperfecta (AI) in 2009 (Parry et al., 19200525). At least four missense variants, three nonsense variants, and one frameshift variant have been reported in humans. Variants in this gene have been reported in at least 10 probands in 2 publications (19200525, 19200527). Variants in this gene segregated with disease in 33 additional family members. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by several lines of experimental evidence including the expression of CNNM4 in retina and incisors in mice (19200525, 19200527), enamel defects similar to AI in a mouse model (24339795), along with rescue studies in zebrafish (19200527). In summary, CNNM4 is definitively associated with autosomal recessive Jalili syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Jalili syndromeAR

Manifestation: Dental; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 3236352; 15173235; 19200525; 19200527; 20706282

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNNM4 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 454

Inborn genetic diseasesTotal: 103

Jalili syndromeTotal: 69

not specifiedTotal: 66

CNNM4-related disorderTotal: 55

Retinal dystrophyTotal: 10

Retinitis pigmentosaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020184.4. 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	167 clinvar	2 clinvar	178
missense	4 clinvar	9 clinvar	255 clinvar	9 clinvar		277
nonsense	8 clinvar	3 clinvar				11
start loss	1 clinvar					1
frameshift	16 clinvar	7 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	3 clinvar			10
Total	32	23	269	176	2	502

Highest pathogenic variant AF is 0.000039652692

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020184.4	RefSeq	NP_064569.3	7	MANE Select
ENST00000377075.3	Ensembl	ENSP00000366275.2	7	MANE Select
ENST00000930282.1	Ensembl	ENSP00000600341.1	7	Standard
ENST00000930282.2	Ensembl	ENSP00000600341.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cnnm4b	Danio rerio	Structure: retinal ganglion cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

cnnm4b

Danio rerio

Structure: retinal ganglion cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
magnesium ion homeostasis
sodium ion transmembrane transport
response to stimulus
metal ion homeostasis

Molecular Function

protein binding
sodium ion transmembrane transporter activity
magnesium ion transmembrane transporter activity

Cellular Component

integral component of membrane
basolateral plasma membrane
dendrite
protein-containing complex
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377075
Coding exons: 7
Length: 50990
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.37	307	448	0.685	0.0000298	5065
Missense (PolyPhen)		67	133.83	0.50063		1510
Synonymous	-0.363	208	201	1.03	0.0000141	1633
Loss of Function	1.78	14	23.3	0.602	0.00000131	276

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000033	0.000033	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions (By similarity). May play a role in biomineralization and retinal function. {ECO:0000250, ECO:0000269|PubMed:19200525, ECO:0000269|PubMed:19200527}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.330
RVIS EVS: -1.15
RVIS percentile EVS: 6.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.795

Gene Damage Prediction

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