2-96816842-C-T

Variant names:

• chr2-96816842-C-T
• rs865847530
• NM_017623.5:c.565C>T

Variant summary

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

The NM_017623.5(CNNM3):​c.565C>T​(p.Arg189Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,051,230 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.630
• 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 0 ACMG points.

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.565C>T	p.Arg189Cys	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.565C>T	p.Arg189Cys	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.565C>T	p.Arg189Cys	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.565C>T	p.Arg189Cys	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.565C>T	p.Arg189Cys	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 88 AN: 147004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000675

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: 0.0000303

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 34 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 37 AN: 904116 Hom.: 1 Cov.: 30 AF XY: 0.0000447 AC XY: 19 AN XY: 425184

African (AFR) AF: 0.00105 AC: 18 AN: 17172

American (AMR) AF: 0.00 AC: 0 AN: 3188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6940

East Asian (EAS) AF: 0.00 AC: 0 AN: 7348

South Asian (SAS) AF: 0.00 AC: 0 AN: 18180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1966

European-Non Finnish (NFE) AF: 0.0000185 AC: 15 AN: 810532

Other (OTH) AF: 0.000127 AC: 4 AN: 31420

GnomAD4 genome AF: 0.000612 AC: 90 AN: 147114 Hom.: 0 Cov.: 32 AF XY: 0.000628 AC XY: 45 AN XY: 71650

African (AFR) AF: 0.00212 AC: 87 AN: 40958

American (AMR) AF: 0.0000674 AC: 1 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66004

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.000427 Hom.: 0

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	0.31
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.63
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.56		Gain of catalytic residue at W190 (P = 0.0021)
MVP		0.63
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.47
gMVP		0.68
Mutation Taster		=66/34	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: rs865847530; hg19: chr2-97482579;