2-96816764-C-T

Variant names:

• chr2-96816764-C-T
• rs1338666997
• NM_017623.5:c.487C>T

Variant summary

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

The NM_017623.5(CNNM3):​c.487C>T​(p.Pro163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000785 in 1,019,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CNNM3 NM_017623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• 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=0.4185226).

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.487C>T	p.Pro163Ser	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.487C>T	p.Pro163Ser	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.487C>T	p.Pro163Ser	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
	CNNM3	ENST00000947263.1		c.487C>T	p.Pro163Ser	missense	Exon 1 of 8	ENSP00000617322.1
	CNNM3	ENST00000947265.1		c.487C>T	p.Pro163Ser	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 146974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

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: 0.00

Gnomad OTH AF: 0.000494

GnomAD4 exome AF: 0.00000573 AC: 5 AN: 872484 Hom.: 0 Cov.: 30 AF XY: 0.00000491 AC XY: 2 AN XY: 407512

African (AFR) AF: 0.0000608 AC: 1 AN: 16440

American (AMR) AF: 0.00 AC: 0 AN: 2310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6032

East Asian (EAS) AF: 0.00 AC: 0 AN: 5286

South Asian (SAS) AF: 0.0000558 AC: 1 AN: 17910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1816

European-Non Finnish (NFE) AF: 0.00000380 AC: 3 AN: 788702

Other (OTH) AF: 0.00 AC: 0 AN: 29530

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 146974 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71500

African (AFR) AF: 0.0000489 AC: 2 AN: 40892

American (AMR) AF: 0.00 AC: 0 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66022

Other (OTH) AF: 0.000494 AC: 1 AN: 2024

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

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	0.21
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.20
MutPred		0.41		Loss of loop (P = 0.0031)
MVP		0.48
ClinPred		0.99	D
GERP RS		3.5
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.63
Mutation Taster		=71/29	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: rs1338666997; hg19: chr2-97482501;