Genetic Variant NM_017623.5:c.256T>C (chr2-96816533-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_017623.5(CNNM3):c.256T>C(p.Cys86Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,353,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CNNM3
NM_017623.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.477

Publications

0 publications found

Variant links:

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 links:

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

CNNM3-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.2686517).

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.256T>C	p.Cys86Arg	missense	Exon 1 of 8	NP_060093.3
	CNNM3	NM_199078.3		c.256T>C	p.Cys86Arg	missense	Exon 1 of 7	NP_951060.1	Q8NE01-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNNM3	ENST00000305510.4	TSL:1 MANE Select	c.256T>C	p.Cys86Arg	missense	Exon 1 of 8	ENSP00000305449.3	Q8NE01-1
CNNM3	ENST00000947263.1		c.256T>C	p.Cys86Arg	missense	Exon 1 of 8	ENSP00000617322.1
CNNM3	ENST00000947265.1		c.256T>C	p.Cys86Arg	missense	Exon 1 of 8	ENSP00000617324.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151478

Hom.:

Cov.:

show subpopulations

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1202108

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

587898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24074

American (AMR)

AF:

0.00

AC:

AN:

11650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17810

East Asian (EAS)

AF:

0.0000366

AC:

AN:

27334

South Asian (SAS)

AF:

0.00

AC:

AN:

49822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3388

European-Non Finnish (NFE)

AF:

0.0000183

AC:

AN:

985824

Other (OTH)

AF:

0.00

AC:

AN:

48210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151478

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73976

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41314

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.044

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.69

PhyloP100

-0.48

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.7

REVEL

Benign

0.28

Sift

Uncertain

0.010

Sift4G

Benign

0.31

Polyphen

0.85

Vest4

0.11

MutPred

0.36

Gain of disorder (P = 0.0193)

MVP

0.49

ClinPred

0.21

GERP RS

2.6

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.9

Varity_R

0.64

gMVP

0.59

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over