10-102918568-C-T

Variant names:

Variant summary

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

The NM_017649.5(CNNM2):c.88C>T(p.Arg30Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,584,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.40

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:

ENSG00000286575 (HGNC:):

ENSG00000286575 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 the CNNM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.4105 (above the threshold of 3.09). Trascript score misZ: 5.0056 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.117658675).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00019 (29/152244) while in subpopulation AFR AF= 0.000577 (24/41566). AF 95% confidence interval is 0.000398. There are 0 homozygotes in gnomad4. There are 16 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 rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 7		NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 2		NP_951059.1	Q9H8M5-3
LOC107984265	NR_160733.1 link	n.-233G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM2	ENST00000369878.9 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 2	1		ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000433628.2 link	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 7	2		ENSP00000392875.2	Q9H8M5-2
ENSG00000286575	ENST00000652934.1 link	n.-233G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000208

AC:

AN:

191892

Hom.:

AF XY:

0.0000280

AC XY:

AN XY:

107194

show subpopulations

Gnomad AFR exome

AF:

0.000375

Gnomad AMR exome

AF:

0.0000343

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:

0.0000140

AC:

AN:

1432486

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

711482

show subpopulations

Gnomad4 AFR exome

AF:

0.000456

Gnomad4 AMR exome

AF:

0.0000487

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:

0.0000676

GnomAD4 genome

AF:

0.000190

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000223

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>T (p.R30C) alteration is located in exon 1 (coding exon 1) of the CNNM2 gene. This alteration results from a C to T substitution at nucleotide position 88, causing the arginine (R) at amino acid position 30 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Renal hypomagnesemia 6;C4225333:Hypomagnesemia, seizures, and intellectual disability 1

Uncertain:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 30 of the CNNM2 protein (p.Arg30Cys). This variant is present in population databases (rs540558653, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CNNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2178214). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.47

N;N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.041

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.24

MutPred

0.31

Gain of catalytic residue at S32 (P = 0.0267);Gain of catalytic residue at S32 (P = 0.0267);Gain of catalytic residue at S32 (P = 0.0267);

MVP

0.093

ClinPred

0.24

GERP RS

5.0

Varity_R

0.17

gMVP

0.50

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