rs114702742

chr3-184352781-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004366.6(CLCN2):c.2173C>T(p.Arg725Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,613,196 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R725Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (4 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.262

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009712398).
• BP6: Variant 3-184352781-G-A is Benign according to our data. Variant chr3-184352781-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 217779.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 = 0.00394 (600/152356) while in subpopulation AFR AF= 0.0128 (532/41586). AF 95% confidence interval is 0.0119. There are 4 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 600 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN2	NM_004366.6	c.2173C>T	p.Arg725Trp	missense_variant	19/24	ENST00000265593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN2	ENST00000265593.9	c.2173C>T	p.Arg725Trp	missense_variant	19/24	1	NM_004366.6	P1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152238 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00100 AC: 250 AN: 249636 Hom.: 1 AF XY: 0.000738 AC XY: 100 AN XY: 135450

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000467 AC: 682 AN: 1460840 Hom.: 4 Cov.: 32 AF XY: 0.000407 AC XY: 296 AN XY: 726728

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000572

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152356 Hom.: 4 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74494

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000970 Hom.: 0

Bravo AF: 0.00453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 11, 2016	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jul 12, 2021	- -

CLCN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.97	D;D;.;.
Vest4		0.59
MVP		0.88
MPC		0.49
ClinPred		0.031	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs114702742; hg19: chr3-184070569;