Genetic Variant CNNM3:p.Ala294Gly (chr2-96817158-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017623.5(CNNM3):c.881C>G(p.Ala294Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 151,770 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)

Consequence

CNNM3
NM_017623.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27869982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM3	NM_017623.5 link	c.881C>G	p.Ala294Gly	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.881C>G	p.Ala294Gly	missense_variant	Exon 1 of 8	1	NM_017623.5	ENSP00000305449.3		Q8NE01-1
CNNM3	ENST00000377060.7 link	c.881C>G	p.Ala294Gly	missense_variant	Exon 1 of 7	2		ENSP00000366260.3		Q8NE01-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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

Cov.:

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000861

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.881C>G (p.A294G) alteration is located in exon 1 (coding exon 1) of the CNNM3 gene. This alteration results from a C to G substitution at nucleotide position 881, causing the alanine (A) at amino acid position 294 to be replaced by a glycine (G). 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

0.22

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

1.1

L;L

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.076

T;D

Polyphen

0.94

P;P

Vest4

0.23

MutPred

0.68

Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.29

ClinPred

0.94

GERP RS

2.6

Varity_R

0.37

gMVP

0.49

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