Genetic Variant CNNM3:p.Leu267Val (chr2-96817076-C-G) – 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.799C>G(p.Leu267Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,352,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

CNNM3
NM_017623.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.845

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=0.34797683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM3	NM_017623.5 link	c.799C>G	p.Leu267Val	missense_variant	Exon 1 of 8	ENST00000305510.4	NP_060093.3	Q8NE01-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM3	ENST00000305510.4 link	c.799C>G	p.Leu267Val	missense_variant	Exon 1 of 8	1	NM_017623.5	ENSP00000305449.3	Q8NE01-1
CNNM3	ENST00000377060.7 link	c.799C>G	p.Leu267Val	missense_variant	Exon 1 of 7	2		ENSP00000366260.3	Q8NE01-2
CNNM3-DT	ENST00000824521.1 link	n.50-3501G>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

151050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

8.32e-7

AC:

AN:

1201428

Hom.:

Cov.:

AF XY:

0.00000170

AC XY:

AN XY:

587554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23470

American (AMR)

AF:

0.0000906

AC:

AN:

11036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16886

East Asian (EAS)

AF:

0.00

AC:

AN:

26390

South Asian (SAS)

AF:

0.00

AC:

AN:

51486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3838

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

991670

Other (OTH)

AF:

0.00

AC:

AN:

48644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000265

AC:

AN:

151050

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41296

American (AMR)

AF:

0.000263

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67614

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.799C>G (p.L267V) 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 799, causing the leucine (L) at amino acid position 267 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.044

.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.84

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.052

T;D

Polyphen

0.31

B;B

Vest4

0.20

MutPred

0.55

Gain of glycosylation at T266 (P = 0.1304);Gain of glycosylation at T266 (P = 0.1304);

MVP

0.11

ClinPred

0.15

GERP RS

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.37

Mutation Taster

=95/5

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

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2-96817076-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over