chr2-96761033-G-T

Variant names:

• chr2-96761033-G-T
• rs1171352404
• NM_020184.4:c.34G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020184.4(CNNM4):​c.34G>T​(p.Gly12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000247 in 1,215,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: CNNM4 NM_020184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.34G>T	p.Gly12Cys	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.34G>T	p.Gly12Cys	missense	Exon 1 of 7	ENSP00000366275.2	Q6P4Q7-1
	CNNM4	ENST00000930282.1		c.34G>T	p.Gly12Cys	missense	Exon 1 of 7	ENSP00000600341.1
	CNNM4	ENST00000966765.1		c.34G>T	p.Gly12Cys	missense	Exon 1 of 8	ENSP00000636824.1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000188 AC: 2 AN: 1066032 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 503418

African (AFR) AF: 0.00 AC: 0 AN: 22032

American (AMR) AF: 0.00 AC: 0 AN: 7652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13324

East Asian (EAS) AF: 0.00 AC: 0 AN: 24920

South Asian (SAS) AF: 0.00 AC: 0 AN: 19400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2980

European-Non Finnish (NFE) AF: 0.00000220 AC: 2 AN: 907876

Other (OTH) AF: 0.00 AC: 0 AN: 42170

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149752 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41158

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67056

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.097	T
Sift4G	Uncertain	0.032	D
Polyphen		0.85	P
Vest4		0.37
MutPred		0.36		Loss of disorder (P = 0.0291)
MVP		0.71
MPC		1.1
ClinPred		0.34	T
GERP RS		1.7
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.23
gMVP		0.49
Mutation Taster		=97/3	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: rs1171352404; hg19: chr2-97426770;