rs12411886

Variant names:

• chr10-102925542-C-A
• rs12411886
• NM_017649.5:c.1621+5441C>A

Variant summary

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

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_017649.5(CNNM2):​c.1621+5441C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0832 in 152,120 control chromosomes in the GnomAD database, including 797 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 0.083 (797 hom., cov: 31)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315
• Publications: 34 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.1621+5441C>A		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.1621+5441C>A		intron_variant	Intron 1 of 6		NP_951058.1
CNNM2	NM_199077.3	c.1622-1803C>A		intron_variant	Intron 1 of 1		NP_951059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.1621+5441C>A		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.1622-1803C>A		intron_variant	Intron 1 of 1	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.1621+5441C>A		intron_variant	Intron 1 of 6	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.0832 AC: 12645 AN: 152002 Hom.: 794 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0947

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

GnomAD4 genome AF: 0.0832 AC: 12655 AN: 152120 Hom.: 797 Cov.: 31 AF XY: 0.0857 AC XY: 6372 AN XY: 74362

African (AFR) AF: 0.0213 AC: 884 AN: 41514

American (AMR) AF: 0.132 AC: 2021 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 242 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1430 AN: 5172

South Asian (SAS) AF: 0.183 AC: 884 AN: 4820

European-Finnish (FIN) AF: 0.0747 AC: 790 AN: 10578

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6161 AN: 67982

Other (OTH) AF: 0.0980 AC: 207 AN: 2112

Alfa AF: 0.0916 Hom.: 634

Bravo AF: 0.0849

Asia WGS AF: 0.196 AC: 680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.38
PhyloP100		0.32
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: rs12411886; hg19: chr10-104685299;