10-102918613-G-T

Position:

chr10-102918613-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. 13/20 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

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]

CNNM2 links:

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=0.24669933).

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
CNNM2	NM_017649.5 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/7
CNNM2	NM_199077.3 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/8	1	NM_017649.5	P4	Q9H8M5-1
CNNM2	ENST00000369875.3 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/2	1			Q9H8M5-3
CNNM2	ENST00000433628.2 linkuse as main transcript	c.133G>T	p.Ala45Ser	missense_variant	1/7	2		A1	Q9H8M5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000677

AC:

AN:

147782

Hom.:

AF XY:

0.0000124

AC XY:

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:

AN:

1397396

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

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.:

ExAC

AF:

0.0000104

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The 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 submitter

clinical testing

GeneDx

Aug 04, 2022

Not 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

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;.;.

Eigen

Benign

-0.074

Eigen_PC

Benign

0.023

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.78

T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.96

N;N;N;N;N

PrimateAI

Pathogenic

0.90

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over