rs114702742

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004366.6(CLCN2):c.2173C>T(p.Arg725Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,613,196 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R725Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 4 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.262

Publications

7 publications found

Variant links:

Genes affected

CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

CLCN2 Gene-Disease associations (from GenCC):

leukoencephalopathy with mild cerebellar ataxia and white matter edema
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
epilepsy, idiopathic generalized, susceptibility to, 11
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
familial hyperaldosteronism type II
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CLCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009712398).

BP6

Variant 3-184352781-G-A is Benign according to our data. Variant chr3-184352781-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 217779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00394 (600/152356) while in subpopulation AFR AF = 0.0128 (532/41586). AF 95% confidence interval is 0.0119. There are 4 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.2173C>T	p.Arg725Trp	missense_variant	Exon 19 of 24	ENST00000265593.9	NP_004357.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 link	c.2173C>T	p.Arg725Trp	missense_variant	Exon 19 of 24	1	NM_004366.6	ENSP00000265593.4

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

600

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00100

AC:

250

AN:

249636

AF XY:

0.000738

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.000467

AC:

682

AN:

1460840

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

296

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.0117

AC:

393

AN:

33480

American (AMR)

AF:

0.00105

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000572

AC:

AN:

52480

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000130

AC:

144

AN:

1111958

Other (OTH)

AF:

0.00124

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00394

AC:

600

AN:

152356

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0128

AC:

532

AN:

41586

American (AMR)

AF:

0.00294

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68036

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLCN2: BS1, BS2 -

Jul 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Benign:1Other:1

Jul 12, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

CLCN2-related disorder

Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.2

M;.;.;M

PhyloP100

0.26

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.97

D;D;.;.

Vest4

0.59

MVP

0.88

MPC

0.49

ClinPred

0.031

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over