rs144164281

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_004366.6(CLCN2):c.2240G>A(p.Arg747His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 1.86

Publications

5 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010873437).

BP6

Variant 3-184352474-C-T is Benign according to our data. Variant chr3-184352474-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 217780.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 = 0.000795 (121/152276) while in subpopulation AFR AF = 0.00253 (105/41562). AF 95% confidence interval is 0.00213. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2240G>A	p.Arg747His	missense	Exon 20 of 24	NP_004357.3
CLCN2	NM_001171087.3		c.2189G>A	p.Arg730His	missense	Exon 20 of 24	NP_001164558.1	P51788-3
CLCN2	NM_001171089.3		c.2240G>A	p.Arg747His	missense	Exon 20 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.2240G>A	p.Arg747His	missense	Exon 20 of 24	ENSP00000265593.4	P51788-1
CLCN2	ENST00000344937.11	TSL:1	c.2189G>A	p.Arg730His	missense	Exon 20 of 24	ENSP00000345056.7	P51788-3
CLCN2	ENST00000430397.5	TSL:1	n.*706G>A		non_coding_transcript_exon	Exon 10 of 13	ENSP00000396231.1	H7C0Q8

Frequencies

GnomAD3 genomes

AF:

0.000776

AC:

118

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000316

AC:

AN:

249940

AF XY:

0.000310

show subpopulations

Gnomad AFR exome

AF:

0.00186

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

233

AN:

1460900

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

726726

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

33480

American (AMR)

AF:

0.000515

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000557

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52780

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1111844

Other (OTH)

AF:

0.000364

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

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:

0.000795

AC:

121

AN:

152276

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41562

American (AMR)

AF:

0.000327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000359

Hom.:

Bravo

AF:

0.000952

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000329

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000416

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Intellectual disability (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.083

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.011

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.0

PhyloP100

1.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.6

REVEL

Benign

0.28

Sift

Benign

0.12

Sift4G

Benign

0.15

Polyphen

0.0020

Vest4

0.26

MVP

0.91

MPC

0.36

ClinPred

0.016

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.47

Mutation Taster

=74/26

polymorphism

(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

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