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GeneBe

10-102918613-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_017649.5(CNNM2):c.133G>T(p.Ala45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,397,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A45E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

2
1
16

Clinical Significance

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

Conservation

PhyloP100: 2.77
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CNNM2
BP4
Computational evidence support a benign effect (MetaRNN=0.24669933).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000293 (41/1397396) while in subpopulation NFE AF= 0.0000361 (39/1081300). AF 95% confidence interval is 0.000027. There are 0 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome 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.133G>T p.Ala45Ser missense_variant 1/8 ENST00000369878.9
CNNM2NM_199076.3 linkuse as main transcriptc.133G>T p.Ala45Ser missense_variant 1/7
CNNM2NM_199077.3 linkuse as main transcriptc.133G>T p.Ala45Ser missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM2ENST00000369878.9 linkuse as main transcriptc.133G>T p.Ala45Ser missense_variant 1/81 NM_017649.5 P4Q9H8M5-1
CNNM2ENST00000369875.3 linkuse as main transcriptc.133G>T p.Ala45Ser missense_variant 1/21 Q9H8M5-3
CNNM2ENST00000433628.2 linkuse as main transcriptc.133G>T p.Ala45Ser missense_variant 1/72 A1Q9H8M5-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000677
AC:
1
AN:
147782
Hom.:
0
AF XY:
0.0000124
AC XY:
1
AN XY:
80700
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000171
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000293
AC:
41
AN:
1397396
Hom.:
0
Cov.:
32
AF XY:
0.0000246
AC XY:
17
AN XY:
690082
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000361
Gnomad4 OTH exome
AF:
0.0000346
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000104
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 GeneticsDec 13, 2022The c.133G>T (p.A45S) alteration is located in exon 1 (coding exon 1) of the CNNM2 gene. This alteration results from a G to T substitution at nucleotide position 133, causing the alanine (A) at amino acid position 45 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 04, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
0.011
T
BayesDel_noAF
Benign
-0.22
Cadd
Benign
19
Dann
Uncertain
0.99
DEOGEN2
Benign
0.016
T;.;.
Eigen
Benign
-0.074
Eigen_PC
Benign
0.023
FATHMM_MKL
Benign
0.077
N
LIST_S2
Benign
0.78
T;T;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.25
T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.0
N;N;N
MutationTaster
Benign
0.96
N;N;N;N;N
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.29
N;N;N
REVEL
Benign
0.081
Sift
Benign
0.16
T;D;T
Sift4G
Benign
0.37
T;T;T
Polyphen
0.61
P;.;P
Vest4
0.20
MutPred
0.31
Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP
0.082
ClinPred
0.36
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.6
Varity_R
0.13
gMVP
0.38

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: rs755515176; hg19: chr10-104678370; API