10-102918595-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_017649.5(CNNM2):c.115G>A(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,565,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.35

Publications

1 publications found

Variant links:

Genes affected

CNNM2 (HGNC:103): (cyclin and CBS domain divalent metal cation transport mediator 2) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

CNNM2 Gene-Disease associations (from GenCC):

hypomagnesemia, seizures, and intellectual disability 1
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
renal hypomagnesemia 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial primary hypomagnesemia with normocalciuria and normocalcemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CNNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26177257).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000854 (13/152306) while in subpopulation AFR AF = 0.000289 (12/41582). AF 95% confidence interval is 0.000166. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 7		NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 2		NP_951059.1	Q9H8M5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM2	ENST00000369878.9 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 2	1		ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000433628.2 link	c.115G>A	p.Gly39Arg	missense_variant	Exon 1 of 7	2		ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

165650

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000158

Gnomad AMR exome

AF:

0.0000387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000991

AC:

AN:

1413282

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

699636

show subpopulations

African (AFR)

AF:

0.000229

AC:

AN:

30608

American (AMR)

AF:

0.0000533

AC:

AN:

37542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24882

East Asian (EAS)

AF:

0.00

AC:

AN:

36470

South Asian (SAS)

AF:

0.00

AC:

AN:

80938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5180

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090946

Other (OTH)

AF:

0.0000854

AC:

AN:

58518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41582

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.00000902

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.115G>A (p.G39R) alteration is located in exon 1 (coding exon 1) of the CNNM2 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the glycine (G) at amino acid position 39 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 39 of the CNNM2 protein (p.Gly39Arg). This variant is present in population databases (rs765571636, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CNNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1918583). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.077

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.85

T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

2.3

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.84

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0090

D;D;D

Sift4G

Benign

0.087

T;T;T

Polyphen

0.012

B;.;B

Vest4

0.26

MutPred

0.37

Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);

MVP

0.043

ClinPred

0.25

GERP RS

5.0

PromoterAI

0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.43

gMVP

0.58

Mutation Taster

=81/19

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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10-102918595-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over