chr3-184353787-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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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

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	UniProt
CLCN2	NM_004366.6	MANE Select	c.1730G>A	p.Arg577Gln	missense	Exon 16 of 24	NP_004357.3
CLCN2	NM_001171087.3		c.1679G>A	p.Arg560Gln	missense	Exon 16 of 24	NP_001164558.1	P51788-3
CLCN2	NM_001171089.3		c.1730G>A	p.Arg577Gln	missense	Exon 16 of 23	NP_001164560.1	P51788-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.1730G>A	p.Arg577Gln	missense	Exon 16 of 24	ENSP00000265593.4	P51788-1
CLCN2	ENST00000344937.11	TSL:1	c.1679G>A	p.Arg560Gln	missense	Exon 16 of 24	ENSP00000345056.7	P51788-3
CLCN2	ENST00000430397.5	TSL:1	n.*196G>A		non_coding_transcript_exon	Exon 6 of 13	ENSP00000396231.1	H7C0Q8

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cerebral palsy (1)

CLCN2-related disorder (1)

Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)

not specified (1)

Epilepsy, idiopathic generalized, susceptibility to, 11 (1)

Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.061

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.8

PhyloP100

5.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.75

REVEL

Uncertain

0.52

Sift

Benign

0.28

Sift4G

Benign

0.29

Polyphen

0.94

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over