3-184353113-C-T

Position:

chr3-184353113-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004366.6(CLCN2):c.2063G>A(p.Arg688Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,614,124 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 33)

Exomes 𝑓: 0.022 ( 410 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.57

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024506748).

BP6

Variant 3-184353113-C-T is Benign according to our data. Variant chr3-184353113-C-T is described in ClinVar as [Benign]. Clinvar id is 217777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184353113-C-T is described in Lovd as [Likely_benign]. Variant chr3-184353113-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2342/152312) while in subpopulation NFE AF= 0.0233 (1582/68016). AF 95% confidence interval is 0.0223. There are 26 homozygotes in gnomad4. There are 1090 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2342 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.2063G>A	p.Arg688Gln	missense_variant	18/24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 link	c.2063G>A	p.Arg688Gln	missense_variant	18/24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2341

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00413

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0344

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0233

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.0151

AC:

3792

AN:

251402

Hom.:

AF XY:

0.0153

AC XY:

2078

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00401

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00297

Gnomad FIN exome

AF:

0.0332

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0217

AC:

31733

AN:

1461812

Hom.:

410

Cov.:

AF XY:

0.0211

AC XY:

15377

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00338

Gnomad4 AMR exome

AF:

0.00622

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00272

Gnomad4 FIN exome

AF:

0.0329

Gnomad4 NFE exome

AF:

0.0254

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0154

AC:

2342

AN:

152312

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1090

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00411

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0344

Gnomad4 NFE

AF:

0.0233

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.0191

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0152

AC:

1839

EpiCase

AF:

0.0216

EpiControl

AF:

0.0192

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CLCN2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2025	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 05, 2015

- -

Epilepsy, idiopathic generalized, susceptibility to, 11

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.0

DANN

Benign

0.94

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

L;.;.;L

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.44

N;N;N;N

REVEL

Benign

0.095

Sift

Benign

0.44

T;T;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.020

B;B;.;.

Vest4

0.069

MPC

0.33

ClinPred

0.0072

GERP RS

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.39

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

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