chr10-102918593-G-A

Position:

chr10-102918593-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_017649.5(CNNM2):c.113G>A(p.Arg38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,564,724 control chromosomes in the GnomAD database, including 2,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.048 ( 182 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2012 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.46

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 Benign. Variant got -19 ACMG points.

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=0.0015188456).

BP6

Variant 10-102918593-G-A is Benign according to our data. Variant chr10-102918593-G-A is described in ClinVar as [Benign]. Clinvar id is 298635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102918593-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CNNM2	NM_017649.5 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/7
CNNM2	NM_199077.3 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/8	1	NM_017649.5	P4	Q9H8M5-1
CNNM2	ENST00000369875.3 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/2	1			Q9H8M5-3
CNNM2	ENST00000433628.2 linkuse as main transcript	c.113G>A	p.Arg38Gln	missense_variant	1/7	2		A1	Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.0484

AC:

7366

AN:

152116

Hom.:

182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0455

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0633

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0479

GnomAD3 exomes

AF:

0.0419

AC:

6884

AN:

164396

Hom.:

191

AF XY:

0.0414

AC XY:

3762

AN XY:

90914

show subpopulations

Gnomad AFR exome

AF:

0.0599

Gnomad AMR exome

AF:

0.0248

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.0604

Gnomad NFE exome

AF:

0.0587

Gnomad OTH exome

AF:

0.0468

GnomAD4 exome

AF:

0.0504

AC:

71153

AN:

1412494

Hom.:

2012

Cov.:

AF XY:

0.0494

AC XY:

34539

AN XY:

699284

show subpopulations

Gnomad4 AFR exome

AF:

0.0493

Gnomad4 AMR exome

AF:

0.0265

Gnomad4 ASJ exome

AF:

0.0312

Gnomad4 EAS exome

AF:

0.000192

Gnomad4 SAS exome

AF:

0.0179

Gnomad4 FIN exome

AF:

0.0584

Gnomad4 NFE exome

AF:

0.0558

Gnomad4 OTH exome

AF:

0.0458

GnomAD4 genome

AF:

0.0485

AC:

7378

AN:

152230

Hom.:

182

Cov.:

AF XY:

0.0472

AC XY:

3515

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0455

Gnomad4 AMR

AF:

0.0335

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.0633

Gnomad4 NFE

AF:

0.0567

Gnomad4 OTH

AF:

0.0493

Alfa

AF:

0.0482

Hom.:

Bravo

AF:

0.0456

TwinsUK

AF:

0.0483

AC:

179

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.0342

AC:

128

ESP6500EA

AF:

0.0469

AC:

346

ExAC

AF:

0.0343

AC:

3804

Asia WGS

AF:

0.0160

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Renal hypomagnesemia 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;.;.

Eigen

Benign

-0.051

Eigen_PC

Benign

0.070

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.96

N;N;N;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.63

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.79

P;.;P

Vest4

0.040

ClinPred

0.088

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.23

gMVP

0.39

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