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GeneBe

10-102918593-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/18 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:3

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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant where missense usually causes diseases, CNNM2
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/exons MANE UniProt
CNNM2NM_017649.5 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/8 ENST00000369878.9
CNNM2NM_199076.3 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/7
CNNM2NM_199077.3 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM2ENST00000369878.9 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/81 NM_017649.5 P4Q9H8M5-1
CNNM2ENST00000369875.3 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/21 Q9H8M5-3
CNNM2ENST00000433628.2 linkuse as main transcriptc.113G>A p.Arg38Gln missense_variant 1/72 A1Q9H8M5-2

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
GnomAD3 exomes
AF:
0.0419
AC:
6884
AN:
164396
Hom.:
191
AF XY:
0.0414
AC XY:
3762
AN XY:
90914
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 SAS exome
AF:
0.0185
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
Gnomad4 AMR exome
AF:
0.0265
Gnomad4 ASJ exome
AF:
0.0312
Gnomad4 EAS exome
AF:
0.000192
Gnomad4 SAS exome
AF:
0.0179
Gnomad4 FIN exome
AF:
0.0584
Gnomad4 NFE exome
AF:
0.0558
Gnomad4 OTH exome
AF:
0.0458
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
Gnomad4 AMR
AF:
0.0335
Gnomad4 ASJ
AF:
0.0337
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.0155
Gnomad4 FIN
AF:
0.0633
Gnomad4 NFE
AF:
0.0567
Gnomad4 OTH
AF:
0.0493
Alfa
AF:
0.0482
Hom.:
45
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:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
Renal hypomagnesemia 6 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
MutationTaster
Benign
0.96
N;N;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

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