Genetic Variant NM_017649.5:c.119T>A (chr10-102918599-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_017649.5(CNNM2):c.119T>A(p.Ile40Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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 links:

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ACMG classification

Classification made for transcript

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=0.18735036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNNM2	NM_017649.5 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 8	ENST00000369878.9	NP_060119.3	Q9H8M5-1
CNNM2	NM_199076.3 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 7		NP_951058.1	Q9H8M5-2
CNNM2	NM_199077.3 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 2		NP_951059.1	Q9H8M5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNNM2	ENST00000369878.9 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 8	1	NM_017649.5	ENSP00000358894.3	Q9H8M5-1
CNNM2	ENST00000369875.3 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 2	1		ENSP00000358891.3	Q9H8M5-3
CNNM2	ENST00000433628.2 link	c.119T>A	p.Ile40Asn	missense_variant	Exon 1 of 7	2		ENSP00000392875.2	Q9H8M5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1409730

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.18e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jun 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.018

T;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.73

T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.97

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.12

T;D;T

Sift4G

Benign

0.073

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.17

MutPred

0.41

Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);

MVP

0.043

ClinPred

0.17

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.31

gMVP

0.77

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over