NM_017649.5:c.1621+1285A>G

Variant names:

• chr10-102921386-A-G
• rs17115213
• NM_017649.5:c.1621+1285A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017649.5(CNNM2):​c.1621+1285A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 152,252 control chromosomes in the GnomAD database, including 850 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 0.091 (850 hom., cov: 32)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• Publications: 20 publications found

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: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

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 = 0.266 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	NM_017649.5	MANE Select	c.1621+1285A>G		intron	N/A	NP_060119.3
	CNNM2	NM_199076.3		c.1621+1285A>G		intron	N/A	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.1621+1285A>G		intron	N/A	NP_951059.1	Q9H8M5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.1621+1285A>G		intron	N/A	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.1621+1285A>G		intron	N/A	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.1621+1285A>G		intron	N/A	ENSP00000640891.1

Frequencies

GnomAD3 genomes AF: 0.0909 AC: 13835 AN: 152134 Hom.: 845 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.0910 AC: 13854 AN: 152252 Hom.: 850 Cov.: 32 AF XY: 0.0929 AC XY: 6917 AN XY: 74448

African (AFR) AF: 0.0464 AC: 1926 AN: 41538

American (AMR) AF: 0.138 AC: 2104 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3468

East Asian (EAS) AF: 0.278 AC: 1440 AN: 5172

South Asian (SAS) AF: 0.185 AC: 890 AN: 4822

European-Finnish (FIN) AF: 0.0759 AC: 806 AN: 10616

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0910 AC: 6187 AN: 68026

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0941 Hom.: 649

Bravo AF: 0.0940

Asia WGS AF: 0.200 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.8
DANN	Benign	0.69
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17115213; hg19: chr10-104681143;