10-103053140-A-G

Variant names:

• chr10-103053140-A-G
• rs10883824
• NM_017649.5:c.1766-1189A>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.1766-1189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 152,062 control chromosomes in the GnomAD database, including 12,420 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 0.40 (12420 hom., cov: 32)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.581
• Publications: 13 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 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.1766-1189A>G		intron	N/A	NP_060119.3
	CNNM2	NM_199076.3		c.1766-1189A>G		intron	N/A	NP_951058.1	Q9H8M5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.1766-1189A>G		intron	N/A	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000970832.1		c.1766-1189A>G		intron	N/A	ENSP00000640891.1
	CNNM2	ENST00000433628.2	TSL:2	c.1766-1189A>G		intron	N/A	ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60994 AN: 151942 Hom.: 12405 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.401 AC: 61049 AN: 152062 Hom.: 12420 Cov.: 32 AF XY: 0.399 AC XY: 29619 AN XY: 74326

African (AFR) AF: 0.376 AC: 15567 AN: 41454

American (AMR) AF: 0.402 AC: 6137 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1498 AN: 3466

East Asian (EAS) AF: 0.486 AC: 2516 AN: 5176

South Asian (SAS) AF: 0.395 AC: 1906 AN: 4826

European-Finnish (FIN) AF: 0.365 AC: 3849 AN: 10558

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28252 AN: 67982

Other (OTH) AF: 0.415 AC: 878 AN: 2114

Alfa AF: 0.407 Hom.: 3543

Bravo AF: 0.404

Asia WGS AF: 0.403 AC: 1397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.51
DANN	Benign	0.48
PhyloP100		-0.58
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: rs10883824; hg19: chr10-104812897;