Genetic Variant CNNM2:c.1621+54035T>A (chr10-102974136-T-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.1621+54035T>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 152,064 control chromosomes in the GnomAD database, including 12,865 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 ( 12865 hom., cov: 32)

Consequence

CNNM2
NM_017649.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.30

Publications

8 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 = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.1621+54035T>A		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.1621+54035T>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.1621+54035T>A		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3		Q9H8M5-1
CNNM2	ENST00000433628.2 link	c.1621+54035T>A		intron_variant	Intron 1 of 6	2		ENSP00000392875.2		Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61949

AN:

151946

Hom.:

12852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.438

Gnomad EAS

AF:

0.559

Gnomad SAS

AF:

0.449

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.418

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:

62005

AN:

152064

Hom.:

12865

Cov.:

AF XY:

0.406

AC XY:

30205

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.378

AC:

15660

AN:

41452

American (AMR)

AF:

0.401

AC:

6120

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

1516

AN:

3464

East Asian (EAS)

AF:

0.559

AC:

2885

AN:

5162

South Asian (SAS)

AF:

0.449

AC:

2166

AN:

4824

European-Finnish (FIN)

AF:

0.368

AC:

3900

AN:

10586

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.418

AC:

28417

AN:

67978

Other (OTH)

AF:

0.422

AC:

892

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1843

3686

5529

7372

9215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.422

Hom.:

1700

Bravo

AF:

0.408

Asia WGS

AF:

0.467

AC:

1619

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

0.32

(source)

DANN

Benign

0.48

PhyloP100

-1.3

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