rs2228292

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2154G>C(p.Glu718Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,200 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E718A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 32)

Exomes 𝑓: 0.022 ( 408 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.547

Publications

14 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=0.004565805).

BP6

Variant 3-184352800-C-G is Benign according to our data. Variant chr3-184352800-C-G is described in ClinVar as Benign. ClinVar VariationId is 217778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2344/152370) while in subpopulation NFE AF = 0.0233 (1583/68034). AF 95% confidence interval is 0.0223. There are 26 homozygotes in GnomAd4. There are 1089 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.2154G>C	p.Glu718Asp	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.2154G>C	p.Glu718Asp	missense_variant	Exon 19 of 24	1	NM_004366.6	ENSP00000265593.4

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2343

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0343

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0233

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0150

AC:

3754

AN:

249834

AF XY:

0.0152

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.00507

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0332

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.0217

AC:

31660

AN:

1460830

Hom.:

408

Cov.:

AF XY:

0.0211

AC XY:

15337

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33480

American (AMR)

AF:

0.00617

AC:

276

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86254

European-Finnish (FIN)

AF:

0.0328

AC:

1721

AN:

52518

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0254

AC:

28218

AN:

1111898

Other (OTH)

AF:

0.0168

AC:

1012

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1674

3347

5021

6694

8368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1044

2088

3132

4176

5220

<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:

0.0154

AC:

2344

AN:

152370

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1089

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00413

AC:

172

AN:

41598

American (AMR)

AF:

0.0103

AC:

158

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00310

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0343

AC:

365

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0233

AC:

1583

AN:

68034

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

242

363

484

605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0155

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0151

AC:

1830

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

May 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.23

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.080

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.0046

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.13

N;.;.;N

PhyloP100

-0.55

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.020

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.34

T;T;T;T

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.14

MutPred

0.076

Gain of glycosylation at S716 (P = 0.0354);.;.;Gain of glycosylation at S716 (P = 0.0354);

MPC

0.26

ClinPred

0.0015

GERP RS

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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