chr10-103085115-T-C

Variant names:

• chr10-103085115-T-C
• rs7092200
• NM_017649.5:c.*7935T>C

Variant summary

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

The NM_017649.5(CNNM2):​c.*7935T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,920 control chromosomes in the GnomAD database, including 13,591 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 0.42 (13588 hom., cov: 31)
  • Exomes 𝑓: 0.36 (3 hom.)
• Consequence: CNNM2 NM_017649.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 15 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017649.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	NM_017649.5	MANE Select	c.*7935T>C		3_prime_UTR	Exon 8 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.*7935T>C		3_prime_UTR	Exon 7 of 7	NP_951058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.*7935T>C		3_prime_UTR	Exon 8 of 8	ENSP00000358894.3

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63723 AN: 151774 Hom.: 13573 Cov.: 31

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.357 AC: 10 AN: 28 Hom.: 3 Cov.: 0 AF XY: 0.300 AC XY: 6 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.350 AC: 7 AN: 20

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.420 AC: 63777 AN: 151892 Hom.: 13588 Cov.: 31 AF XY: 0.416 AC XY: 30894 AN XY: 74230

African (AFR) AF: 0.391 AC: 16186 AN: 41446

American (AMR) AF: 0.422 AC: 6438 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3468

East Asian (EAS) AF: 0.486 AC: 2492 AN: 5126

South Asian (SAS) AF: 0.401 AC: 1927 AN: 4804

European-Finnish (FIN) AF: 0.377 AC: 3968 AN: 10532

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.437 AC: 29702 AN: 67938

Other (OTH) AF: 0.435 AC: 917 AN: 2110

Alfa AF: 0.427 Hom.: 7280

Bravo AF: 0.423

Asia WGS AF: 0.410 AC: 1423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.31
PhyloP100		-1.5
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: rs7092200; hg19: chr10-104844872;