rs1590243044

Variant names:

• chr10-102918605-AGGCGGCTGCGG-A
• rs1590243044
• NM_017649.5:c.135_145delGGGGCGGCTGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017649.5(CNNM2):​c.135_145delGGGGCGGCTGC​(p.Gly46AlafsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNNM2 NM_017649.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102918605-AGGCGGCTGCGG-A is Pathogenic according to our data. Variant chr10-102918605-AGGCGGCTGCGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817123.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.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 2		NP_951059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.135_145delGGGGCGGCTGC	p.Gly46AlafsTer21	frameshift_variant	Exon 1 of 7	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 694288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 06, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.135_145del11 variant in the CNNM2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.135_145del11 variant causes a frameshift starting with codon Glycine 46, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Gly46AlafsX21. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135_145del11 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.135_145del11 as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1590243044; hg19: chr10-104678362;