3-184353275-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004366.6(CLCN2):c.2003C>G(p.Thr668Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,082 control chromosomes in the GnomAD database, including 229,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. T668I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.54 ( 23661 hom., cov: 33)

Exomes 𝑓: 0.52 ( 205804 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.49

Publications

36 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=4.0687833E-6).

BP6

Variant 3-184353275-G-C is Benign according to our data. Variant chr3-184353275-G-C is described in ClinVar as Benign. ClinVar VariationId is 217776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004366.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN2	NM_004366.6	MANE Select	c.2003C>G	p.Thr668Ser	missense	Exon 17 of 24	NP_004357.3
CLCN2	NM_001171087.3		c.1952C>G	p.Thr651Ser	missense	Exon 17 of 24	NP_001164558.1
CLCN2	NM_001171089.3		c.2003C>G	p.Thr668Ser	missense	Exon 17 of 23	NP_001164560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.2003C>G	p.Thr668Ser	missense	Exon 17 of 24	ENSP00000265593.4
CLCN2	ENST00000344937.11	TSL:1	c.1952C>G	p.Thr651Ser	missense	Exon 17 of 24	ENSP00000345056.7
CLCN2	ENST00000430397.5	TSL:1	n.*469C>G		non_coding_transcript_exon	Exon 7 of 13	ENSP00000396231.1

Frequencies

GnomAD3 genomes

AF:

0.545

AC:

82836

AN:

152014

Hom.:

23634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.431

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.0969

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.558

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.538

GnomAD2 exomes

AF:

0.473

AC:

118966

AN:

251278

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.324

Gnomad ASJ exome

AF:

0.477

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.426

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.522

AC:

762052

AN:

1460948

Hom.:

205804

Cov.:

AF XY:

0.521

AC XY:

378757

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.679

AC:

22724

AN:

33474

American (AMR)

AF:

0.335

AC:

15003

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.472

AC:

12334

AN:

26132

East Asian (EAS)

AF:

0.0694

AC:

2754

AN:

39696

South Asian (SAS)

AF:

0.474

AC:

40850

AN:

86244

European-Finnish (FIN)

AF:

0.432

AC:

23005

AN:

53250

Middle Eastern (MID)

AF:

0.516

AC:

2978

AN:

5768

European-Non Finnish (NFE)

AF:

0.550

AC:

611666

AN:

1111284

Other (OTH)

AF:

0.509

AC:

30738

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

20485

40970

61455

81940

102425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16912

33824

50736

67648

84560

<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:

0.545

AC:

82902

AN:

152134

Hom.:

23661

Cov.:

AF XY:

0.530

AC XY:

39424

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.684

AC:

28393

AN:

41522

American (AMR)

AF:

0.431

AC:

6589

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

1591

AN:

3470

East Asian (EAS)

AF:

0.0967

AC:

499

AN:

5160

South Asian (SAS)

AF:

0.462

AC:

2230

AN:

4824

European-Finnish (FIN)

AF:

0.411

AC:

4343

AN:

10566

Middle Eastern (MID)

AF:

0.572

AC:

166

AN:

290

European-Non Finnish (NFE)

AF:

0.553

AC:

37580

AN:

67980

Other (OTH)

AF:

0.532

AC:

1123

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1877

3754

5631

7508

9385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.508

Hom.:

5541

Bravo

AF:

0.551

TwinsUK

AF:

0.541

AC:

2005

ALSPAC

AF:

0.553

AC:

2132

ESP6500AA

AF:

0.680

AC:

2994

ESP6500EA

AF:

0.550

AC:

4729

ExAC

AF:

0.489

AC:

59427

Asia WGS

AF:

0.318

AC:

1112

AN:

3478

EpiCase

AF:

0.553

EpiControl

AF:

0.559

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.3

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.070

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.041

MetaRNN

Benign

0.0000041

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.47

PhyloP100

1.5

PrimateAI

Benign

0.32

PROVEAN

Benign

0.92

REVEL

Benign

0.16

Sift

Benign

0.83

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.031

MutPred

0.23

Loss of glycosylation at P667 (P = 0.0121)

MPC

0.26

ClinPred

0.0018

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.23

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over