rs12219027

Variant names:

• chr10-103051446-T-C
• rs12219027
• NM_017649.5:c.1765+1596T>C

Variant summary

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

The NM_017649.5(CNNM2):​c.1765+1596T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.096 in 148,810 control chromosomes in the GnomAD database, including 875 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 0.096 (875 hom., cov: 31)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.988
• Publications: 18 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.1765+1596T>C		intron_variant	Intron 2 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.1765+1596T>C		intron_variant	Intron 2 of 6		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.1765+1596T>C		intron_variant	Intron 2 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.1765+1596T>C		intron_variant	Intron 2 of 6	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.0959 AC: 14259 AN: 148686 Hom.: 869 Cov.: 31

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0960 AC: 14280 AN: 148810 Hom.: 875 Cov.: 31 AF XY: 0.0981 AC XY: 7128 AN XY: 72674

African (AFR) AF: 0.0620 AC: 2486 AN: 40122

American (AMR) AF: 0.142 AC: 2111 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 243 AN: 3440

East Asian (EAS) AF: 0.287 AC: 1425 AN: 4970

South Asian (SAS) AF: 0.187 AC: 881 AN: 4712

European-Finnish (FIN) AF: 0.0775 AC: 781 AN: 10082

Middle Eastern (MID) AF: 0.0778 AC: 21 AN: 270

European-Non Finnish (NFE) AF: 0.0905 AC: 6095 AN: 67364

Other (OTH) AF: 0.108 AC: 221 AN: 2046

Alfa AF: 0.0893 Hom.: 91

Bravo AF: 0.0979

Asia WGS AF: 0.198 AC: 687 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.18
PhyloP100		-0.99
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: rs12219027; hg19: chr10-104811203;