Genetic Variant CNNM2:p.Ala21Thr (chr10-102918541-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_017649.5(CNNM2):c.61G>A(p.Ala21Thr) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, ClinGen
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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27239805).

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.61G>A	p.Ala21Thr	missense	Exon 1 of 8	NP_060119.3
CNNM2	NM_199076.3		c.61G>A	p.Ala21Thr	missense	Exon 1 of 7	NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3		c.61G>A	p.Ala21Thr	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.61G>A	p.Ala21Thr	missense	Exon 1 of 8	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3	TSL:1	c.61G>A	p.Ala21Thr	missense	Exon 1 of 2	ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000970832.1		c.61G>A	p.Ala21Thr	missense	Exon 1 of 7	ENSP00000640891.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1449244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720914

African (AFR)

AF:

0.00

AC:

AN:

31990

American (AMR)

AF:

0.00

AC:

AN:

43806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25778

East Asian (EAS)

AF:

0.00

AC:

AN:

38538

South Asian (SAS)

AF:

0.00

AC:

AN:

84962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108494

Other (OTH)

AF:

0.00

AC:

AN:

59792

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal hypomagnesemia 6;C4225333:Hypomagnesemia, seizures, and intellectual disability 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.018

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.28

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.14

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0215)

MVP

0.093

ClinPred

0.87

GERP RS

4.9

PromoterAI

-0.082

Neutral

(source)

Varity_R

0.37

gMVP

0.53

Mutation Taster

=56/44

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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