10-102918623-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_017649.5(CNNM2):c.143T>C(p.Leu48Pro) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNNM2 NM_017649.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNNM2
• PP5: Variant 10-102918623-T-C is Pathogenic according to our data. Variant chr10-102918623-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 996041.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32629347).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNNM2	NM_017649.5	c.143T>C	p.Leu48Pro	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3	c.143T>C	p.Leu48Pro	missense_variant	1/7
CNNM2	NM_199077.3	c.143T>C	p.Leu48Pro	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9	c.143T>C	p.Leu48Pro	missense_variant	1/8	1	NM_017649.5	P4
CNNM2	ENST00000369875.3	c.143T>C	p.Leu48Pro	missense_variant	1/2	1
CNNM2	ENST00000433628.2	c.143T>C	p.Leu48Pro	missense_variant	1/7	2		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypomagnesemia, seizures, and intellectual disability 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Physiology, Radboud University Medical Center

Jan 22, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.043	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.74	N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.38	B;.;P
Vest4		0.43
MutPred		0.57		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.63
ClinPred		0.42	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.34
gMVP		0.89

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: rs1845510486; hg19: chr10-104678380;