10-102918575-G-T

Position:

chr10-102918575-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM2PP2BP4_StrongBP6_ModerateBS1

The NM_017649.5(CNNM2):c.95G>T(p.Ser32Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000702 in 1,581,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.02

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 Benign. Variant got -7 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=0.01654169).

BP6

Variant 10-102918575-G-T is Benign according to our data. Variant chr10-102918575-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2909399.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000679 (97/1428862) while in subpopulation NFE AF= 0.0000291 (32/1099782). AF 95% confidence interval is 0.0000211. There are 0 homozygotes in gnomad4_exome. There are 47 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CNNM2	NM_017649.5 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/8	ENST00000369878.9
CNNM2	NM_199076.3 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/7
CNNM2	NM_199077.3 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNNM2	ENST00000369878.9 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/8	1	NM_017649.5	P4	Q9H8M5-1
CNNM2	ENST00000369875.3 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/2	1			Q9H8M5-3
CNNM2	ENST00000433628.2 linkuse as main transcript	c.95G>T	p.Ser32Ile	missense_variant	1/7	2		A1	Q9H8M5-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

187004

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

104310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000704

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1428862

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

709248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000248

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.0000291

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000602

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.0063

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

0.77

N;N;N;N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.58

N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0070

D;D;D

Sift4G

Benign

0.23

T;T;T

Polyphen

0.037

B;.;B

Vest4

0.17

MutPred

0.31

Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);

MVP

0.043

ClinPred

0.25

GERP RS

4.2

Varity_R

0.24

gMVP

0.53

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