NM_017623.5:c.799C>G

Variant names:

• chr2-96817076-C-G
• rs1015625758
• NM_017623.5:c.799C>G

Variant summary

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

The NM_017623.5(CNNM3):​c.799C>G​(p.Leu267Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,352,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.845
• Publications: 0 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: 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=0.34797683).

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.799C>G	p.Leu267Val	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.799C>G	p.Leu267Val	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.799C>G	p.Leu267Val	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.799C>G	p.Leu267Val	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.799C>G	p.Leu267Val	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 151050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.32e-7 AC: 1 AN: 1201428 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 587554

African (AFR) AF: 0.00 AC: 0 AN: 23470

American (AMR) AF: 0.0000906 AC: 1 AN: 11036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16886

East Asian (EAS) AF: 0.00 AC: 0 AN: 26390

South Asian (SAS) AF: 0.00 AC: 0 AN: 51486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3838

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 991670

Other (OTH) AF: 0.00 AC: 0 AN: 48644

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 151050 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73786

African (AFR) AF: 0.00 AC: 0 AN: 41296

American (AMR) AF: 0.000263 AC: 4 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10194

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67614

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

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	0.11
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.84
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.052	T
Polyphen		0.31	B
Vest4		0.20
MutPred		0.55		Gain of glycosylation at T266 (P = 0.1304)
MVP		0.11
ClinPred		0.15	T
GERP RS		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.37
Mutation Taster		=95/5	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: rs1015625758; hg19: chr2-97482813;