10-103013607-C-T

Variant names:

• chr10-103013607-C-T
• rs11191514
• NM_017649.5:c.1622-36100C>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.1622-36100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 152,002 control chromosomes in the GnomAD database, including 884 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 0.095 (884 hom., cov: 32)
• Consequence: CNNM2 NM_017649.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 33 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=-0.68).
• 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.1622-36100C>T		intron_variant	Intron 1 of 7	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.1622-36100C>T		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.1622-36100C>T		intron_variant	Intron 1 of 7	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000433628.2	c.1622-36100C>T		intron_variant	Intron 1 of 6	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14428 AN: 151884 Hom.: 879 Cov.: 32

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0764

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.0951 AC: 14448 AN: 152002 Hom.: 884 Cov.: 32 AF XY: 0.0969 AC XY: 7200 AN XY: 74272

African (AFR) AF: 0.0606 AC: 2511 AN: 41462

American (AMR) AF: 0.138 AC: 2110 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 268 AN: 3466

East Asian (EAS) AF: 0.277 AC: 1430 AN: 5168

South Asian (SAS) AF: 0.184 AC: 887 AN: 4816

European-Finnish (FIN) AF: 0.0764 AC: 807 AN: 10564

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

European-Non Finnish (NFE) AF: 0.0909 AC: 6178 AN: 67980

Other (OTH) AF: 0.105 AC: 220 AN: 2096

Alfa AF: 0.0918 Hom.: 2102

Bravo AF: 0.0985

Asia WGS AF: 0.200 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.2
DANN	Benign	0.77
PhyloP100		1.2
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: rs11191514; hg19: chr10-104773364;