rs12413409

Variant names:

• chr10-102959339-G-A
• rs12413409
• NM_017649.5:c.1621+39238G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017649.5(CNNM2):​c.1621+39238G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0944 in 152,230 control chromosomes in the GnomAD database, including 881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.094 (881 hom., cov: 31)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.442
• Publications: 162 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-102959339-G-A is Benign according to our data. Variant chr10-102959339-G-A is described in ClinVar as Benign. ClinVar VariationId is 1569780.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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+39238G>A		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.1621+39238G>A		intron_variant	Intron 1 of 6		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.1621+39238G>A		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.1621+39238G>A		intron_variant	Intron 1 of 6	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14356 AN: 152112 Hom.: 876 Cov.: 31

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.0944 AC: 14375 AN: 152230 Hom.: 881 Cov.: 31 AF XY: 0.0964 AC XY: 7173 AN XY: 74414

African (AFR) AF: 0.0592 AC: 2459 AN: 41546

American (AMR) AF: 0.138 AC: 2108 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1434 AN: 5182

South Asian (SAS) AF: 0.184 AC: 888 AN: 4826

European-Finnish (FIN) AF: 0.0757 AC: 803 AN: 10604

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0909 AC: 6180 AN: 68018

Other (OTH) AF: 0.104 AC: 220 AN: 2108

Alfa AF: 0.0959 Hom.: 2894

Bravo AF: 0.0978

Asia WGS AF: 0.199 AC: 688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		0.44
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: rs12413409; hg19: chr10-104719096;