Genetic Variant NM_017649.5:c.97C>G (chr10-102918577-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017649.5(CNNM2):c.97C>G(p.Leu33Val) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L33F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.101

Publications

0 publications found

Variant links:

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

CNNM2 links:

ENSG00000286575 (HGNC:):

ENSG00000286575 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1258704).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNNM2	NM_017649.5	MANE Select	c.97C>G	p.Leu33Val	missense	Exon 1 of 8	NP_060119.3
CNNM2	NM_199076.3		c.97C>G	p.Leu33Val	missense	Exon 1 of 7	NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3		c.97C>G	p.Leu33Val	missense	Exon 1 of 2	NP_951059.1	Q9H8M5-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNNM2	ENST00000369878.9	TSL:1 MANE Select	c.97C>G	p.Leu33Val	missense	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3	TSL:1	c.97C>G	p.Leu33Val	missense	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000970832.1		c.97C>G	p.Leu33Val	missense	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.016

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

0.10

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.12

REVEL

Benign

0.099

Sift

Benign

0.076

Sift4G

Benign

0.43

Polyphen

0.0040

Vest4

0.079

MutPred

0.17

Loss of helix (P = 0.0626)

MVP

0.043

ClinPred

0.12

GERP RS

3.2

PromoterAI

0.28

Neutral

(source)

Varity_R

0.12

gMVP

0.39

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over