rs2078754724

Variant names:

• chr2-96761012-G-T
• rs2078754724
• NM_020184.4:c.13G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020184.4(CNNM4):​c.13G>T​(p.Gly5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,023,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CNNM4 NM_020184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.263
• Publications: 0 publications found

Genes affected

CNNM4 (HGNC:105): (cyclin and CBS domain divalent metal cation transport mediator 4) 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]

CNNM4 Gene-Disease associations (from GenCC):

• Jalili syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36601615).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM4	NM_020184.4	MANE Select	c.13G>T	p.Gly5Cys	missense	Exon 1 of 7	NP_064569.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM4	ENST00000377075.3	TSL:1 MANE Select	c.13G>T	p.Gly5Cys	missense	Exon 1 of 7	ENSP00000366275.2	Q6P4Q7-1
	CNNM4	ENST00000930282.1		c.13G>T	p.Gly5Cys	missense	Exon 1 of 7	ENSP00000600341.1
	CNNM4	ENST00000966765.1		c.13G>T	p.Gly5Cys	missense	Exon 1 of 8	ENSP00000636824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 7 AN: 1023582 Hom.: 0 Cov.: 30 AF XY: 0.0000104 AC XY: 5 AN XY: 482284

African (AFR) AF: 0.00 AC: 0 AN: 20724

American (AMR) AF: 0.00 AC: 0 AN: 6436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11660

East Asian (EAS) AF: 0.00 AC: 0 AN: 20888

South Asian (SAS) AF: 0.00 AC: 0 AN: 19022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2616

European-Non Finnish (NFE) AF: 0.00000680 AC: 6 AN: 882726

Other (OTH) AF: 0.0000254 AC: 1 AN: 39342

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000936 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.013
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.26
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		0.94	P
Vest4		0.17
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0676)
MVP		0.80
MPC		1.1
ClinPred		0.60	D
GERP RS		2.6
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.37
gMVP		0.72
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2078754724; hg19: chr2-97426749;