rs786205909

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP5_Moderate

The NM_017649.5(CNNM2):c.364G>A(p.Glu122Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.41

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 5 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.

PP5

Variant 10-102918844-G-A is Pathogenic according to our data. Variant chr10-102918844-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192323.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 7		NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 2		NP_951059.1	Q9H8M5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM2	ENST00000369878.9 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 2	1		ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000433628.2 link	c.364G>A	p.Glu122Lys	missense_variant	Exon 1 of 7	2		ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000488

AC:

AN:

204770

Hom.:

AF XY:

0.00

AC XY:

AN XY:

111340

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:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000139

AC:

AN:

1434142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711168

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:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypomagnesemia, seizures, and intellectual disability 1

Pathogenic:2

Oct 12, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.79

Sift

Benign

0.030

D;D;D

Sift4G

Uncertain

0.042

D;D;D

Polyphen

0.98

D;.;D

Vest4

0.72

MutPred

0.46

Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);

MVP

0.043

ClinPred

0.97

GERP RS

3.9

Varity_R

0.30

gMVP

0.98

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