10-102918593-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CNNM2
• 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	UniProt
CNNM2	NM_017649.5	c.113G>A	p.Arg38Gln	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.113G>A	p.Arg38Gln	missense_variant	1/7
CNNM2	NM_199077.3	c.113G>A	p.Arg38Gln	missense_variant	1/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7366 AN: 152116 Hom.: 182 Cov.: 32

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

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.: 32 AF XY: 0.0494 AC XY: 34539 AN XY: 699284

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.: 32 AF XY: 0.0472 AC XY: 3515 AN XY: 74426

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.: 45

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: 57 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

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	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.96	N;N;N;N;N
PrimateAI	Pathogenic	0.89	D
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	T
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

Other links and lift over

dbSNP: rs76057237; hg19: chr10-104678350; COSMIC: COSV63996349; COSMIC: COSV63996349;