Variant 10-102918623-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP5BP4

The NM_017649.5(CNNM2):c.143T>C(p.Leu48Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.10

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

PP5

Variant 10-102918623-T-C is Pathogenic according to our data. Variant chr10-102918623-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 996041.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.32629347). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CNNM2	NM_017649.5 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/7
CNNM2	NM_199077.3 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/8	1	NM_017649.5	P4	Q9H8M5-1
CNNM2	ENST00000369875.3 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/2	1			Q9H8M5-3
CNNM2	ENST00000433628.2 linkuse as main transcript	c.143T>C	p.Leu48Pro	missense_variant	1/7	2		A1	Q9H8M5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypomagnesemia, seizures, and intellectual disability 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Physiology, Radboud University Medical Center

Jan 22, 2021

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.043

T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.69

T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.74

N;N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.38

B;.;P

Vest4

0.43

MutPred

0.57

Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.63

ClinPred

0.42

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.34

gMVP

0.89

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