rs7071373

Variant names:

• chr10-103012165-A-G
• rs7071373
• NM_017649.5:c.1622-37542A>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.1622-37542A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,044 control chromosomes in the GnomAD database, including 12,859 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 0.41 (12859 hom., cov: 32)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652
• Publications: 7 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.1622-37542A>G		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.1622-37542A>G		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.1622-37542A>G		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.1622-37542A>G		intron_variant	Intron 1 of 6	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61915 AN: 151926 Hom.: 12847 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.408 AC: 61969 AN: 152044 Hom.: 12859 Cov.: 32 AF XY: 0.406 AC XY: 30165 AN XY: 74308

African (AFR) AF: 0.376 AC: 15607 AN: 41474

American (AMR) AF: 0.401 AC: 6133 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1518 AN: 3472

East Asian (EAS) AF: 0.559 AC: 2888 AN: 5168

South Asian (SAS) AF: 0.450 AC: 2168 AN: 4820

European-Finnish (FIN) AF: 0.368 AC: 3879 AN: 10540

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28439 AN: 67976

Other (OTH) AF: 0.421 AC: 888 AN: 2108

Alfa AF: 0.421 Hom.: 1767

Bravo AF: 0.409

Asia WGS AF: 0.470 AC: 1631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-0.65
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: rs7071373; hg19: chr10-104771922;