10-102918595-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_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. 13/20 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

2
2
15

Clinical Significance

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

Conservation

PhyloP100: 2.35
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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNNM2. . Gene score misZ 4.4105 (greater than the threshold 3.09). Trascript score misZ 5.0056 (greater than threshold 3.09). GenCC has associacion of gene with hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNNM2NM_017649.5 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/8 ENST00000369878.9
CNNM2NM_199076.3 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/7
CNNM2NM_199077.3 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM2ENST00000369878.9 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/81 NM_017649.5 P4Q9H8M5-1
CNNM2ENST00000369875.3 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/21 Q9H8M5-3
CNNM2ENST00000433628.2 linkuse as main transcriptc.115G>A p.Gly39Arg missense_variant 1/72 A1Q9H8M5-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152192
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000121
AC:
2
AN:
165650
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
91520
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 SAS 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:
14
AN:
1413282
Hom.:
0
Cov.:
32
AF XY:
0.00000429
AC XY:
3
AN XY:
699636
show subpopulations
Gnomad4 AFR exome
AF:
0.000229
Gnomad4 AMR exome
AF:
0.0000533
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000854
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0000653
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
Bravo
AF:
0.0000907
ExAC
AF:
0.00000902
AC:
1

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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 11, 2021The 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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 25, 2022This 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.016
T;.;.
Eigen
Benign
-0.14
Eigen_PC
Benign
0.077
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.85
T;T;T
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
0.0
N;N;N
MutationTaster
Benign
0.88
D;D;D;D;D
PrimateAI
Pathogenic
0.93
D
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
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.43
gMVP
0.58

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: rs765571636; hg19: chr10-104678352; API