Genetic Variant CNNM2:c.1622-14330C>T (chr10-103035377-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_017649.5(CNNM2):c.1622-14330C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 152,100 control chromosomes in the GnomAD database, including 1,638 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 0.14 ( 1638 hom., cov: 32)

Consequence

CNNM2
NM_017649.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

20 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.1622-14330C>T		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.1622-14330C>T		intron_variant	Intron 1 of 6		NP_951058.1	Q9H8M5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9 link	c.1622-14330C>T		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3		Q9H8M5-1
CNNM2	ENST00000433628.2 link	c.1622-14330C>T		intron_variant	Intron 1 of 6	2		ENSP00000392875.2		Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21083

AN:

151982

Hom.:

1639

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.0694

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.139

AC:

21084

AN:

152100

Hom.:

1638

Cov.:

AF XY:

0.138

AC XY:

10222

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0947

AC:

3930

AN:

41520

American (AMR)

AF:

0.101

AC:

1541

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

702

AN:

3470

East Asian (EAS)

AF:

0.193

AC:

995

AN:

5164

South Asian (SAS)

AF:

0.161

AC:

774

AN:

4820

European-Finnish (FIN)

AF:

0.156

AC:

1650

AN:

10552

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11086

AN:

67974

Other (OTH)

AF:

0.144

AC:

305

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

920

1839

2759

3678

4598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.151

Hom.:

280

Bravo

AF:

0.131

Asia WGS

AF:

0.148

AC:

512

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.48

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