Variant 2-96816680-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017623.5(CNNM3):c.403T>C(p.Trp135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,022,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CNNM3
NM_017623.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.193

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:

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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/exons	MANE	Protein	UniProt
CNNM3	NM_017623.5 linkuse as main transcript	c.403T>C	p.Trp135Arg	missense_variant	1/8	ENST00000305510.4	NP_060093.3	Q8NE01-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNNM3	ENST00000305510.4 linkuse as main transcript	c.403T>C	p.Trp135Arg	missense_variant	1/8	1	NM_017623.5	ENSP00000305449.3		Q8NE01-1
CNNM3	ENST00000377060.7 linkuse as main transcript	c.403T>C	p.Trp135Arg	missense_variant	1/7	2		ENSP00000366260.3		Q8NE01-2

Frequencies

GnomAD3 genomes

AF:

0.000367

AC:

AN:

147088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00132

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:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

875410

Hom.:

Cov.:

AF XY:

0.0000122

AC XY:

AN XY:

408454

show subpopulations

Gnomad4 AFR exome

AF:

0.000784

Gnomad4 AMR exome

AF:

0.000409

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.000367

AC:

AN:

147088

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

AN XY:

71550

show subpopulations

Gnomad4 AFR

AF:

0.00132

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000495

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.403T>C (p.W135R) alteration is located in exon 1 (coding exon 1) of the CNNM3 gene. This alteration results from a T to C substitution at nucleotide position 403, causing the tryptophan (W) at amino acid position 135 to be replaced by an arginine (R). 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

Pathogenic

0.87

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.35

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.38

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.81

L;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.66

P;B

Vest4

0.51

MutPred

0.63

Loss of catalytic residue at W135 (P = 0.0016);Loss of catalytic residue at W135 (P = 0.0016);

MVP

0.27

ClinPred

0.45

GERP RS

1.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.4

Varity_R

0.54

gMVP

0.70

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