chr10-102918613-G-T

Variant names:

• chr10-102918613-G-T
• rs755515176
• NM_017649.5:c.133G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_017649.5(CNNM2):​c.133G>T​(p.Ala45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,397,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A45E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.77
• 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: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24669933).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000293 (41/1397396) while in subpopulation NFE AF = 0.0000361 (39/1081300). AF 95% confidence interval is 0.000027. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.133G>T	p.Ala45Ser	missense	Exon 1 of 8	NP_060119.3
	CNNM2	NM_199076.3		c.133G>T	p.Ala45Ser	missense	Exon 1 of 7	NP_951058.1	Q9H8M5-2
	CNNM2	NM_199077.3		c.133G>T	p.Ala45Ser	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.133G>T	p.Ala45Ser	missense	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
	CNNM2	ENST00000369875.3	TSL:1	c.133G>T	p.Ala45Ser	missense	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
	CNNM2	ENST00000970832.1		c.133G>T	p.Ala45Ser	missense	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000677 AC: 1 AN: 147782 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000293 AC: 41 AN: 1397396 Hom.: 0 Cov.: 32 AF XY: 0.0000246 AC XY: 17 AN XY: 690082

African (AFR) AF: 0.00 AC: 0 AN: 30394

American (AMR) AF: 0.00 AC: 0 AN: 35588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24788

East Asian (EAS) AF: 0.00 AC: 0 AN: 35472

South Asian (SAS) AF: 0.00 AC: 0 AN: 79434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5072

European-Non Finnish (NFE) AF: 0.0000361 AC: 39 AN: 1081300

Other (OTH) AF: 0.0000346 AC: 2 AN: 57872

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000104 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.081
Sift	Benign	0.16	T
Sift4G	Benign	0.37	T
Polyphen		0.61	P
Vest4		0.20
MutPred		0.31		Loss of helix (P = 0.028)
MVP		0.082
ClinPred		0.36	T
GERP RS		4.4
PromoterAI		0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.13
gMVP		0.38
Mutation Taster		=82/18	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: rs755515176; hg19: chr10-104678370;