10-102918580-A-T

Position:

chr10-102918580-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_017649.5(CNNM2):c.100A>T(p.Ser34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 1,576,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNNM2. . Gene score misZ 4.4105 (greater than the threshold 3.09). Trascript score misZ 5.0056 (greater than threshold 3.09). GenCC has associacion of gene with hypomagnesemia, seizures, and intellectual disability 1, familial primary hypomagnesemia with normocalciuria and normocalcemia, renal hypomagnesemia 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.13591662).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000046 (7/152088) while in subpopulation AFR AF= 0.000169 (7/41404). AF 95% confidence interval is 0.000079. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CNNM2	NM_017649.5 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/7
CNNM2	NM_199077.3 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/8	1	NM_017649.5	P4	Q9H8M5-1
CNNM2	ENST00000369875.3 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/2	1			Q9H8M5-3
CNNM2	ENST00000433628.2 linkuse as main transcript	c.100A>T	p.Ser34Cys	missense_variant	1/7	2		A1	Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180654

Hom.:

AF XY:

0.00000993

AC XY:

AN XY:

100730

show subpopulations

Gnomad AFR exome

AF:

0.000280

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1424144

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

706422

show subpopulations

Gnomad4 AFR exome

AF:

0.000196

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2022

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the CNNM2 protein (p.Ser34Cys). This variant is present in population databases (rs748377838, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CNNM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.021

T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.71

T;T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.93

N;N;N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.71

N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.056

T;D;T

Polyphen

0.45

P;.;P

Vest4

0.22

MutPred

0.24

Loss of glycosylation at S34 (P = 0.0204);Loss of glycosylation at S34 (P = 0.0204);Loss of glycosylation at S34 (P = 0.0204);

MVP

0.043

ClinPred

0.12

GERP RS

2.7

Varity_R

0.097

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over