Genetic Variant CNNM3:p.Arg246Leu (chr2-96817014-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017623.5(CNNM3):c.737G>T(p.Arg246Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,368,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

CNNM3
NM_017623.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.498

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM3	NM_017623.5 link	c.737G>T	p.Arg246Leu	missense_variant	Exon 1 of 8	ENST00000305510.4	NP_060093.3	Q8NE01-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM3	ENST00000305510.4 link	c.737G>T	p.Arg246Leu	missense_variant	Exon 1 of 8	1	NM_017623.5	ENSP00000305449.3		Q8NE01-1
CNNM3	ENST00000377060.7 link	c.737G>T	p.Arg246Leu	missense_variant	Exon 1 of 7	2		ENSP00000366260.3		Q8NE01-2

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149502

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000169

AC:

AN:

59014

Hom.:

AF XY:

0.00

AC XY:

AN XY:

34700

show subpopulations

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 SAS exome

AF:

0.0000729

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000328

AC:

AN:

1218590

Hom.:

Cov.:

AF XY:

0.00000333

AC XY:

AN XY:

600588

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000101

Gnomad4 OTH exome

AF:

0.0000419

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72900

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.737G>T (p.R246L) alteration is located in exon 1 (coding exon 1) of the CNNM3 gene. This alteration results from a G to T substitution at nucleotide position 737, causing the arginine (R) at amino acid position 246 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.050

T;D

Polyphen

1.0

D;D

Vest4

0.24

MutPred

0.74

Loss of methylation at R246 (P = 0.0259);Loss of methylation at R246 (P = 0.0259);

MVP

0.54

ClinPred

0.96

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.79

gMVP

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over