chr10-103076290-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017649.5(CNNM2):c.2418+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,550,844 control chromosomes in the GnomAD database, including 123,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12617 hom., cov: 32)

Exomes 𝑓: 0.40 ( 111123 hom. )

Consequence

CNNM2
NM_017649.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.68

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 10-103076290-T-C is Benign according to our data. Variant chr10-103076290-T-C is described in ClinVar as Benign. ClinVar VariationId is 1217370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.2418+20T>C		intron_variant	Intron 7 of 7	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.2352+20T>C		intron_variant	Intron 6 of 6		NP_951058.1	Q9H8M5-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM2	ENST00000369878.9 link	c.2418+20T>C	intron_variant	Intron 7 of 7	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000433628.2 link	c.2352+20T>C	intron_variant	Intron 6 of 6	2		ENSP00000392875.2	Q9H8M5-2
CNNM2	ENST00000475511.1 link	n.472+20T>C	intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.405

AC:

61500

AN:

151944

Hom.:

12603

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.403

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.395

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.412

GnomAD2 exomes

AF:

0.409

AC:

64855

AN:

158444

AF XY:

0.409

show subpopulations

Gnomad AFR exome

AF:

0.393

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.425

Gnomad EAS exome

AF:

0.492

Gnomad FIN exome

AF:

0.367

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.419

GnomAD4 exome

AF:

0.397

AC:

555492

AN:

1398782

Hom.:

111123

Cov.:

AF XY:

0.398

AC XY:

274311

AN XY:

689946

show subpopulations

African (AFR)

AF:

0.386

AC:

12200

AN:

31614

American (AMR)

AF:

0.418

AC:

14943

AN:

35730

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

10600

AN:

25188

East Asian (EAS)

AF:

0.417

AC:

14940

AN:

35800

South Asian (SAS)

AF:

0.407

AC:

32199

AN:

79198

European-Finnish (FIN)

AF:

0.366

AC:

18076

AN:

49392

Middle Eastern (MID)

AF:

0.438

AC:

2409

AN:

5500

European-Non Finnish (NFE)

AF:

0.396

AC:

426510

AN:

1078320

Other (OTH)

AF:

0.407

AC:

23615

AN:

58040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16330

32659

48989

65318

81648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13314

26628

39942

53256

66570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.405

AC:

61554

AN:

152062

Hom.:

12617

Cov.:

AF XY:

0.402

AC XY:

29850

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.388

AC:

16083

AN:

41474

American (AMR)

AF:

0.403

AC:

6160

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1498

AN:

3470

East Asian (EAS)

AF:

0.486

AC:

2515

AN:

5174

South Asian (SAS)

AF:

0.395

AC:

1902

AN:

4820

European-Finnish (FIN)

AF:

0.364

AC:

3846

AN:

10566

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.415

AC:

28233

AN:

67970

Other (OTH)

AF:

0.415

AC:

873

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1901

3801

5702

7602

9503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.415

Hom.:

6311

Bravo

AF:

0.408

Asia WGS

AF:

0.403

AC:

1399

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypomagnesemia, seizures, and intellectual disability 1

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal hypomagnesemia 6

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.2

(source)

DANN

Benign

0.25

PhyloP100

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over