3-184353787-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_004366.6(CLCN2):c.1730G>A(p.Arg577Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,605,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5O:2

Conservation

PhyloP100: 5.01

Publications

15 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09578988).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000454 (69/152130) while in subpopulation AMR AF = 0.00249 (38/15272). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.1730G>A	p.Arg577Gln	missense_variant	Exon 16 of 24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 link	c.1730G>A	p.Arg577Gln	missense_variant	Exon 16 of 24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000329

AC:

AN:

233882

AF XY:

0.000292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000612

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.000153

Gnomad NFE exome

AF:

0.000399

Gnomad OTH exome

AF:

0.000698

GnomAD4 exome

AF:

0.000232

AC:

338

AN:

1453824

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

158

AN XY:

722494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.000508

AC:

AN:

43326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25872

East Asian (EAS)

AF:

0.000507

AC:

AN:

39436

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84758

European-Finnish (FIN)

AF:

0.0000957

AC:

AN:

52250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000252

AC:

279

AN:

1108912

Other (OTH)

AF:

0.000183

AC:

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000454

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41420

American (AMR)

AF:

0.00249

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68030

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000493

Hom.:

Bravo

AF:

0.000374

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLCN2: PM2, BP4 -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 577 of the CLCN2 protein (p.Arg577Gln). This variant is present in population databases (rs137852682, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CLCN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 9039). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CLCN2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CLCN2 function (PMID: 19191339, 23632988). 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. -

Cerebral palsy

Pathogenic:1

Jun 10, 2021

Neurogenetics Research Program, University of Adelaide

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

Jan 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CLCN2 c.1730G>A (p.Arg577Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 233882 control chromosomes, predominantly at a frequency of 0.00061 within the Latino subpopulation in the gnomAD database. c.1730G>A has been reported in the literature in two siblings affected with CLCN2-Related Disorders but did not segregate with disease in that family, meanwhile another apparently pathogenic deletion c.4339-12_4349del23 in SCN1A was found arising de novo in another patient with severe myoclonic epilepsy of infancy in the same family (Saint-Martin_2009). These report(s) do not provide unequivocal conclusions about association of the variant with CLCN2-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of long-lasting closed state of CLCN2 channel via patch clamp recordings in HEK293T cells (Stolting_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19191339, 23632988). ClinVar contains an entry for this variant (Variation ID: 9039). Based on the evidence outlined above, the variant was classified as VUS. -

Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Uncertain:1

Jun 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

CLCN2-related disorder

Uncertain:1

Feb 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CLCN2 c.1730G>A variant is predicted to result in the amino acid substitution p.Arg577Gln. This variant was reported in heterozygous state in two siblings with generalized tonic-clonic seizures (GTCS) and their unaffected father (Saint-Martin et al. 2009. PubMed ID: 19191339). In vitro functional studies suggest that this variant may impact protein function (Saint-Martin et al. 2009. PubMed ID: 19191339; Stölting et al. 2013. PubMed ID: 23632988). This variant is reported in 0.060% of alleles in individuals of Latino descent in gnomAD, which is higher than expected for autosomal dominant disorder. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Epilepsy, idiopathic generalized, susceptibility to, 11

Other:1

Mar 01, 2009

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.096

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.8

L;.;.;L

PhyloP100

5.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.75

N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.29

T;T;T;T

Polyphen

0.94

P;P;.;.

Vest4

0.24

MVP

0.88

MPC

0.54

ClinPred

0.063

GERP RS

5.0

Varity_R

0.059

gMVP

0.47

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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