NM_017649.5:c.2167+990C>T

Variant names:

• chr10-103069712-C-T
• rs1926032
• NM_017649.5:c.2167+990C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017649.5(CNNM2):​c.2167+990C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 152,252 control chromosomes in the GnomAD database, including 627 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 0.073 (627 hom., cov: 33)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 16 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.2167+990C>T		intron_variant	Intron 5 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.2167+990C>T		intron_variant	Intron 5 of 6		NP_951058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.2167+990C>T		intron_variant	Intron 5 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.2167+990C>T		intron_variant	Intron 5 of 6	2		ENSP00000392875.2
CNNM2	ENST00000475511.1	n.287+990C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11165 AN: 152134 Hom.: 619 Cov.: 33

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.0799

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

GnomAD4 genome AF: 0.0735 AC: 11188 AN: 152252 Hom.: 627 Cov.: 33 AF XY: 0.0752 AC XY: 5596 AN XY: 74442

African (AFR) AF: 0.0359 AC: 1490 AN: 41562

American (AMR) AF: 0.119 AC: 1817 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3470

East Asian (EAS) AF: 0.272 AC: 1409 AN: 5174

South Asian (SAS) AF: 0.150 AC: 722 AN: 4818

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0692 AC: 4706 AN: 68014

Other (OTH) AF: 0.0838 AC: 177 AN: 2112

Alfa AF: 0.0668 Hom.: 229

Bravo AF: 0.0771

Asia WGS AF: 0.186 AC: 644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.34
DANN	Benign	0.84
PhyloP100		-1.9
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: rs1926032; hg19: chr10-104829469;