10-102918686-A-G

Position:

• chr10-102918686-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017649.5(CNNM2):​c.206A>G​(p.Asn69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNNM2. . Gene score misZ 4.4105 (greater than the threshold 3.09). Trascript score misZ 5.0056 (greater than threshold 3.09). GenCC has associacion of gene with hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.071730375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM2	NM_017649.5	c.206A>G	p.Asn69Ser	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.206A>G	p.Asn69Ser	missense_variant	1/7
CNNM2	NM_199077.3	c.206A>G	p.Asn69Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.206A>G	p.Asn69Ser	missense_variant	1/8	1	NM_017649.5	P4
CNNM2	ENST00000369875.3	c.206A>G	p.Asn69Ser	missense_variant	1/2	1
CNNM2	ENST00000433628.2	c.206A>G	p.Asn69Ser	missense_variant	1/7	2		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.6
DANN	Benign	0.49
DEOGEN2	Benign	0.011	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N;N;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.40	N;N;N
REVEL	Benign	0.084
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.041
MutPred		0.27		Gain of disorder (P = 0.0897);Gain of disorder (P = 0.0897);Gain of disorder (P = 0.0897);
MVP		0.043
ClinPred		0.068	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.063
gMVP		0.35

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: rs1845515645; hg19: chr10-104678443;