10-102918593-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017649.5(CNNM2):c.113G>T(p.Arg38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypomagnesemia, seizures, and intellectual disability 1
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
renal hypomagnesemia 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial primary hypomagnesemia with normocalciuria and normocalcemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CNNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24150655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 1 of 7		NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3 link	c.113G>T	p.Arg38Leu	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.113G>T	p.Arg38Leu	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 1 of 2	1		ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000433628.2 link	c.113G>T	p.Arg38Leu	missense_variant	Exon 1 of 7	2		ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412516

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699294

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30542

American (AMR)

AF:

0.00

AC:

AN:

37486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24882

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36406

South Asian (SAS)

AF:

0.00

AC:

AN:

80874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090694

Other (OTH)

AF:

0.00

AC:

AN:

58466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.099

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

2.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.25

MutPred

0.33

Loss of methylation at R38 (P = 0.0099);Loss of methylation at R38 (P = 0.0099);Loss of methylation at R38 (P = 0.0099);

MVP

0.043

ClinPred

0.52

GERP RS

4.1

PromoterAI

0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.31

gMVP

0.55

Mutation Taster

=90/10

polymorphism

(source)

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

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10-102918593-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over