10-102918516-G-T

Variant names:

• chr10-102918516-G-T
• NM_017649.5:c.36G>T

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.36G>T​(p.Lys12Asn) 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. 13/20 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: 1.34

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]

ENSG00000286575 (HGNC:):

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 the CNNM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 4.4105 (above the threshold of 3.09). Trascript score misZ: 5.0056 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21850157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3
CNNM2	NM_199076.3	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 7		NP_951058.1
CNNM2	NM_199077.3	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 2		NP_951059.1
LOC107984265	NR_160733.1	n.-181C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNNM2	ENST00000369878.9	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3
CNNM2	ENST00000369875.3	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 2	1		ENSP00000358891.3
CNNM2	ENST00000433628.2	c.36G>T	p.Lys12Asn	missense_variant	Exon 1 of 7	2		ENSP00000392875.2
ENSG00000286575	ENST00000652934.1	n.-181C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.36G>T (p.K12N) 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 36, causing the lysine (K) at amino acid position 12 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.077	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.18	B;.;B
Vest4		0.12
MutPred		0.28		Loss of ubiquitination at K12 (P = 0.0118);Loss of ubiquitination at K12 (P = 0.0118);Loss of ubiquitination at K12 (P = 0.0118);
MVP		0.043
ClinPred		0.50	T
GERP RS		4.0
Varity_R		0.20
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104678273;