10-102918613-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

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. 13/20 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNNM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.24669933).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM2	NM_017649.5	c.133G>T	p.Ala45Ser	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.133G>T	p.Ala45Ser	missense_variant	1/7
CNNM2	NM_199077.3	c.133G>T	p.Ala45Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.133G>T	p.Ala45Ser	missense_variant	1/8	1	NM_017649.5	P4
CNNM2	ENST00000369875.3	c.133G>T	p.Ala45Ser	missense_variant	1/2	1
CNNM2	ENST00000433628.2	c.133G>T	p.Ala45Ser	missense_variant	1/7	2		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000677 AC: 1 AN: 147782 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80700

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.0000346

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000104 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.133G>T (p.A45S) alteration is located in exon 1 (coding exon 1) of the CNNM2 gene. This alteration results from a G to T substitution at nucleotide position 133, causing the alanine (A) at amino acid position 45 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	0.96	N;N;N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.16	T;D;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.61	P;.;P
Vest4		0.20
MutPred		0.31		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.082
ClinPred		0.36	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.13
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs755515176; hg19: chr10-104678370;