10-102918595-G-C

Variant names:

• chr10-102918595-G-C
• rs765571636
• NM_017649.5:c.115G>C

Variant summary

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

The NM_017649.5(CNNM2):​c.115G>C​(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,413,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• 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, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, ClinGen
• 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=0.30130994).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	NM_017649.5	MANE Select	c.115G>C	p.Gly39Arg	missense	Exon 1 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.115G>C	p.Gly39Arg	missense	Exon 1 of 7	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.115G>C	p.Gly39Arg	missense	Exon 1 of 2	NP_951059.1	Q9H8M5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.115G>C	p.Gly39Arg	missense	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.115G>C	p.Gly39Arg	missense	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.115G>C	p.Gly39Arg	missense	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413282 Hom.: 0 Cov.: 32 AF XY: 0.00000429 AC XY: 3 AN XY: 699636

African (AFR) AF: 0.00 AC: 0 AN: 30608

American (AMR) AF: 0.00 AC: 0 AN: 37542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24882

East Asian (EAS) AF: 0.00 AC: 0 AN: 36470

South Asian (SAS) AF: 0.00 AC: 0 AN: 80938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5180

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090946

Other (OTH) AF: 0.00 AC: 0 AN: 58518

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.087	T
Polyphen		0.012	B
Vest4		0.26
MutPred		0.37		Loss of loop (P = 0.0112)
MVP		0.068
ClinPred		0.55	D
GERP RS		5.0
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.58
Mutation Taster		=81/19	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: rs765571636; hg19: chr10-104678352;