chr3-184357688-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004366.6(CLCN2):c.704G>A(p.Arg235Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,614,112 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2O:2

Conservation

PhyloP100: 4.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12657866).

BP6

Variant 3-184357688-C-T is Benign according to our data. Variant chr3-184357688-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9038.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, not_provided=1}. Variant chr3-184357688-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00107 (163/152366) while in subpopulation NFE AF= 0.00146 (99/68026). AF 95% confidence interval is 0.00122. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 7 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.704G>A	p.Arg235Gln	missense_variant	Exon 7 of 24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00112

AC:

282

AN:

251230

Hom.:

AF XY:

0.00107

AC XY:

146

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00140

AC:

2041

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

993

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00242

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152366

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00146

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jul 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Uncertain:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 11, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hyperaldosteronism type II;C2750893:Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, idiopathic generalized, susceptibility to, 11

Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not specified

Benign:1

Jan 03, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLCN2 c.704G>A (p.Arg235Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1614112 control chromosomes (including two homozygotes), predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD v4 database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in CLCN2 causing CLCN2-Related Disorders phenotype. ClinVar contains an entry for this variant (Variation ID: 9038). Based on the evidence outlined above, the variant was classified as likely benign. -

EPILEPSY, JUVENILE MYOCLONIC, SUSCEPTIBILITY TO, 8

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

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.;.;.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.2

M;M;.;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

N;N;N;N;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.024

D;D;D;D;.

Sift4G

Uncertain

0.049

D;T;D;T;.

Polyphen

0.97

D;P;.;.;.

Vest4

0.94

MVP

0.96

MPC

1.1

ClinPred

0.15

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.62

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over