10-102918593-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017649.5(CNNM2):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,564,724 control chromosomes in the GnomAD database, including 2,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.048 ( 182 hom., cov: 32)
Exomes 𝑓: 0.050 ( 2012 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

1
1
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.46
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0015188456).
BP6
Variant 10-102918593-G-A is Benign according to our data. Variant chr10-102918593-G-A is described in ClinVar as [Benign]. Clinvar id is 298635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102918593-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CNNM2NM_017649.5 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 8 ENST00000369878.9 NP_060119.3 Q9H8M5-1
CNNM2NM_199076.3 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 7 NP_951058.1 Q9H8M5-2
CNNM2NM_199077.3 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 2 NP_951059.1 Q9H8M5-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CNNM2ENST00000369878.9 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 8 1 NM_017649.5 ENSP00000358894.3 Q9H8M5-1
CNNM2ENST00000369875.3 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 2 1 ENSP00000358891.3 Q9H8M5-3
CNNM2ENST00000433628.2 linkc.113G>A p.Arg38Gln missense_variant Exon 1 of 7 2 ENSP00000392875.2 Q9H8M5-2

Frequencies

GnomAD3 genomes
AF:
0.0484
AC:
7366
AN:
152116
Hom.:
182
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0455
Gnomad AMI
AF:
0.152
Gnomad AMR
AF:
0.0335
Gnomad ASJ
AF:
0.0337
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0151
Gnomad FIN
AF:
0.0633
Gnomad MID
AF:
0.0446
Gnomad NFE
AF:
0.0567
Gnomad OTH
AF:
0.0479
GnomAD2 exomes
AF:
0.0419
AC:
6884
AN:
164396
AF XY:
0.0414
show subpopulations
Gnomad AFR exome
AF:
0.0599
Gnomad AMR exome
AF:
0.0248
Gnomad ASJ exome
AF:
0.0320
Gnomad EAS exome
AF:
0.000168
Gnomad FIN exome
AF:
0.0604
Gnomad NFE exome
AF:
0.0587
Gnomad OTH exome
AF:
0.0468
GnomAD4 exome
AF:
0.0504
AC:
71153
AN:
1412494
Hom.:
2012
Cov.:
32
AF XY:
0.0494
AC XY:
34539
AN XY:
699284
show subpopulations
Gnomad4 AFR exome
AF:
0.0493
AC:
1505
AN:
30540
Gnomad4 AMR exome
AF:
0.0265
AC:
993
AN:
37484
Gnomad4 ASJ exome
AF:
0.0312
AC:
776
AN:
24882
Gnomad4 EAS exome
AF:
0.000192
AC:
7
AN:
36406
Gnomad4 SAS exome
AF:
0.0179
AC:
1451
AN:
80874
Gnomad4 FIN exome
AF:
0.0584
AC:
2802
AN:
48012
Gnomad4 NFE exome
AF:
0.0558
AC:
60812
AN:
1090678
Gnomad4 Remaining exome
AF:
0.0458
AC:
2680
AN:
58466
Heterozygous variant carriers
0
4241
8482
12722
16963
21204
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
2230
4460
6690
8920
11150
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0485
AC:
7378
AN:
152230
Hom.:
182
Cov.:
32
AF XY:
0.0472
AC XY:
3515
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.0455
AC:
0.0455267
AN:
0.0455267
Gnomad4 AMR
AF:
0.0335
AC:
0.033525
AN:
0.033525
Gnomad4 ASJ
AF:
0.0337
AC:
0.0336982
AN:
0.0336982
Gnomad4 EAS
AF:
0.000387
AC:
0.000386548
AN:
0.000386548
Gnomad4 SAS
AF:
0.0155
AC:
0.015528
AN:
0.015528
Gnomad4 FIN
AF:
0.0633
AC:
0.0632899
AN:
0.0632899
Gnomad4 NFE
AF:
0.0567
AC:
0.0566507
AN:
0.0566507
Gnomad4 OTH
AF:
0.0493
AC:
0.0492891
AN:
0.0492891
Heterozygous variant carriers
0
373
747
1120
1494
1867
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
84
168
252
336
420
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0490
Hom.:
50
Bravo
AF:
0.0456
TwinsUK
AF:
0.0483
AC:
179
ALSPAC
AF:
0.0488
AC:
188
ESP6500AA
AF:
0.0342
AC:
128
ESP6500EA
AF:
0.0469
AC:
346
ExAC
AF:
0.0343
AC:
3804
Asia WGS
AF:
0.0160
AC:
57
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 10, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Renal hypomagnesemia 6 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
T;.;.
Eigen
Benign
-0.051
Eigen_PC
Benign
0.070
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.79
T;T;T
MetaRNN
Benign
0.0015
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N;N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.63
N;N;N
REVEL
Benign
0.19
Sift
Benign
0.11
T;T;T
Sift4G
Benign
0.16
T;T;T
Polyphen
0.79
P;.;P
Vest4
0.040
ClinPred
0.088
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.23
gMVP
0.39
Mutation Taster
=86/14
polymorphism (auto)

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.

Other links and lift over

dbSNP: rs76057237; hg19: chr10-104678350; COSMIC: COSV63996349; COSMIC: COSV63996349; API