dbSNP rs7092200: CNNM2:c.*7935T>C (chr10-103085115-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017649.5(CNNM2):c.*7935T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,920 control chromosomes in the GnomAD database, including 13,591 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 13588 hom., cov: 31)

Exomes 𝑓: 0.36 ( 3 hom. )

Consequence

CNNM2
NM_017649.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.53

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.*7935T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3 link	c.*7935T>C		3_prime_UTR_variant	Exon 7 of 7		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9 link	c.*7935T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_017649.5	ENSP00000358894.3

Frequencies

GnomAD3 genomes

AF:

0.420

AC:

63723

AN:

151774

Hom.:

13573

Cov.:

show subpopulations

Gnomad AFR

AF:

0.390

Gnomad AMI

AF:

0.386

Gnomad AMR

AF:

0.422

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.432

GnomAD4 exome

AF:

0.357

AC:

AN:

Hom.:

Cov.:

AF XY:

0.300

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.350

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.420

AC:

63777

AN:

151892

Hom.:

13588

Cov.:

AF XY:

0.416

AC XY:

30894

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.391

AC:

16186

AN:

41446

American (AMR)

AF:

0.422

AC:

6438

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

1657

AN:

3468

East Asian (EAS)

AF:

0.486

AC:

2492

AN:

5126

South Asian (SAS)

AF:

0.401

AC:

1927

AN:

4804

European-Finnish (FIN)

AF:

0.377

AC:

3968

AN:

10532

Middle Eastern (MID)

AF:

0.476

AC:

139

AN:

292

European-Non Finnish (NFE)

AF:

0.437

AC:

29702

AN:

67938

Other (OTH)

AF:

0.435

AC:

917

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1876

3752

5627

7503

9379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.427

Hom.:

7280

Bravo

AF:

0.423

Asia WGS

AF:

0.410

AC:

1423

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.19

(source)

DANN

Benign

0.31

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(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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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