chr10-102918526-G-GGGCA

Variant names:

• chr10-102918526-G-GGGCA
• NM_017649.5:c.52_55dupGCAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017649.5(CNNM2):​c.52_55dupGCAG​(p.Ala19GlyfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNNM2 NM_017649.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.87
• Publications: 0 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

ENSG00000286575 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102918526-G-GGGCA is Pathogenic according to our data. Variant chr10-102918526-G-GGGCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4074742.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 2		NP_951059.1
LOC107984265	NR_160733.1	n.-195_-192dupTGCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.52_55dupGCAG	p.Ala19GlyfsTer53	frameshift_variant	Exon 1 of 7	2		ENSP00000392875.2
ENSG00000286575	ENST00000652934.1	n.-195_-192dupTGCC		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypomagnesemia 6;C4225333:Hypomagnesemia, seizures, and intellectual disability 1 Pathogenic:1

Jun 18, 2025

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1, PM2; Variant was found in heterozygous state. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr10-104678283;