NM_017649.5:c.112C>G

Variant names:

• chr10-102918592-C-G
• rs1480720023
• NM_017649.5:c.112C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017649.5(CNNM2):​c.112C>G​(p.Arg38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,567,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30461323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 2		NP_951059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.112C>G	p.Arg38Gly	missense_variant	Exon 1 of 7	2		ENSP00000392875.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 700642

African (AFR) AF: 0.00 AC: 0 AN: 30568

American (AMR) AF: 0.00 AC: 0 AN: 37784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24912

East Asian (EAS) AF: 0.00 AC: 0 AN: 36514

South Asian (SAS) AF: 0.00 AC: 0 AN: 81056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1092092

Other (OTH) AF: 0.00 AC: 0 AN: 58584

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		1.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.82	N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.59	T;T;T
Polyphen		0.14	B;.;B
Vest4		0.30
MutPred		0.29		Loss of methylation at R38 (P = 0.0099);Loss of methylation at R38 (P = 0.0099);Loss of methylation at R38 (P = 0.0099);
MVP		0.068
ClinPred		0.44	T
GERP RS		5.0
PromoterAI		-0.046	Neutral
Varity_R		0.35
gMVP		0.58
Mutation Taster		=84/16	polymorphism

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: rs1480720023; hg19: chr10-104678349;