rs71318369

chr3-184357688-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1 O:2
• Conservation: PhyloP100: 4.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12657866).
• BS2: High AC in GnomAd at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN2	NM_004366.6	c.704G>A	p.Arg235Gln	missense_variant	7/24	ENST00000265593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN2	ENST00000265593.9	c.704G>A	p.Arg235Gln	missense_variant	7/24	1	NM_004366.6	P1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152248 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.00107 AC XY: 146 AN XY: 135856

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.: 2 Cov.: 34 AF XY: 0.00137 AC XY: 993 AN XY: 727180

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.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74510

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.: 1

Bravo AF: 0.000903

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Familial hyperaldosteronism type II;C2750893:Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Epilepsy, idiopathic generalized, susceptibility to, 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Epilepsy, juvenile myoclonic 8 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.2	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
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	T
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

Other links and lift over

dbSNP: rs71318369; hg19: chr3-184075476;