Genetic Variant CNNM2:c.1622-54033G>A (chr10-102995674-G-A) – 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.1622-54033G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 148,474 control chromosomes in the GnomAD database, including 12,360 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 0.41 ( 12360 hom., cov: 28)

Consequence

CNNM2
NM_017649.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.680

Publications

23 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=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.1622-54033G>A		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.1622-54033G>A		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.1622-54033G>A		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3		Q9H8M5-1
CNNM2	ENST00000433628.2 link	c.1622-54033G>A		intron_variant	Intron 1 of 6	2		ENSP00000392875.2		Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

60557

AN:

148376

Hom.:

12349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.411

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.490

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.381

Gnomad MID

AF:

0.445

Gnomad NFE

AF:

0.419

Gnomad OTH

AF:

0.419

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

GnomAD4 genome

AF:

0.408

AC:

60606

AN:

148474

Hom.:

12360

Cov.:

AF XY:

0.407

AC XY:

29422

AN XY:

72204

show subpopulations

African (AFR)

AF:

0.381

AC:

15228

AN:

39986

American (AMR)

AF:

0.411

AC:

6041

AN:

14704

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

1508

AN:

3462

East Asian (EAS)

AF:

0.490

AC:

2474

AN:

5052

South Asian (SAS)

AF:

0.432

AC:

2043

AN:

4728

European-Finnish (FIN)

AF:

0.381

AC:

3753

AN:

9846

Middle Eastern (MID)

AF:

0.455

AC:

130

AN:

286

European-Non Finnish (NFE)

AF:

0.419

AC:

28240

AN:

67438

Other (OTH)

AF:

0.422

AC:

870

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1765

3530

5295

7060

8825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.345

Hom.:

1477

Bravo

AF:

0.403

Asia WGS

AF:

0.425

AC:

1475

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.31

(source)

DANN

Benign

0.59

PhyloP100

-0.68

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