NM_017623.5:c.28C>G

Variant names:

• chr2-96816305-C-G
• rs373318478
• NM_017623.5:c.28C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017623.5(CNNM3):​c.28C>G​(p.Arg10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,287,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. R10W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.577
• Publications: 2 publications found

Genes affected

CNNM3 (HGNC:104): (cyclin and CBS domain divalent metal cation transport mediator 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in ion transport; magnesium ion homeostasis; and transmembrane transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CNNM3-DT (HGNC:53592): (CNNM3 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024907023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017623.5. 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
	CNNM3	NM_017623.5	MANE Select	c.28C>G	p.Arg10Gly	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.28C>G	p.Arg10Gly	missense	Exon 1 of 7	NP_951060.1	Q8NE01-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM3	ENST00000305510.4	TSL:1 MANE Select	c.28C>G	p.Arg10Gly	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.28C>G	p.Arg10Gly	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.28C>G	p.Arg10Gly	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000957

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000778 AC: 15 AN: 19272 AF XY: 0.000907

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000470 AC: 534 AN: 1135674 Hom.: 1 Cov.: 31 AF XY: 0.000493 AC XY: 269 AN XY: 545318

African (AFR) AF: 0.00 AC: 0 AN: 23558

American (AMR) AF: 0.00 AC: 0 AN: 10614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14972

East Asian (EAS) AF: 0.00 AC: 0 AN: 27330

South Asian (SAS) AF: 0.00 AC: 0 AN: 33672

European-Finnish (FIN) AF: 0.000312 AC: 8 AN: 25658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3046

European-Non Finnish (NFE) AF: 0.000538 AC: 512 AN: 951328

Other (OTH) AF: 0.000308 AC: 14 AN: 45496

GnomAD4 genome AF: 0.000454 AC: 69 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 29 AN XY: 74188

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000957 AC: 65 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000636 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.000301 AC: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.092
Sift	Benign	0.76	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.20
ClinPred		0.033	T
GERP RS		-0.18
PromoterAI		-0.050	Neutral
Varity_R		0.057
gMVP		0.28
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs373318478; hg19: chr2-97482042; COSMIC: COSV100562618; COSMIC: COSV100562618;