3-184352800-C-G

Variant names:

• chr3-184352800-C-G
• rs2228292
• NM_004366.6:c.2154G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004366.6(CLCN2):​c.2154G>C​(p.Glu718Asp) 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 1,613,200 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E718A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., cov: 32)
  • Exomes 𝑓: 0.022 (408 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.547
• Publications: 14 publications found

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, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004565805).
• BP6: Variant 3-184352800-C-G is Benign according to our data. Variant chr3-184352800-C-G is described in ClinVar as Benign. ClinVar VariationId is 217778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2344/152370) while in subpopulation NFE AF = 0.0233 (1583/68034). AF 95% confidence interval is 0.0223. There are 26 homozygotes in GnomAd4. There are 1089 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	NM_004366.6	MANE Select	c.2154G>C	p.Glu718Asp	missense	Exon 19 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.2103G>C	p.Glu701Asp	missense	Exon 19 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.2154G>C	p.Glu718Asp	missense	Exon 19 of 23	NP_001164560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.2154G>C	p.Glu718Asp	missense	Exon 19 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.2103G>C	p.Glu701Asp	missense	Exon 19 of 24	ENSP00000345056.7
	CLCN2	ENST00000430397.5	TSL:1	n.*620G>C		non_coding_transcript_exon	Exon 9 of 13	ENSP00000396231.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2343 AN: 152252 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0150 AC: 3754 AN: 249834 AF XY: 0.0152

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0217 AC: 31660 AN: 1460830 Hom.: 408 Cov.: 32 AF XY: 0.0211 AC XY: 15337 AN XY: 726714

African (AFR) AF: 0.00338 AC: 113 AN: 33480

American (AMR) AF: 0.00617 AC: 276 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00268 AC: 231 AN: 86254

European-Finnish (FIN) AF: 0.0328 AC: 1721 AN: 52518

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.0254 AC: 28218 AN: 1111898

Other (OTH) AF: 0.0168 AC: 1012 AN: 60384

GnomAD4 genome AF: 0.0154 AC: 2344 AN: 152370 Hom.: 26 Cov.: 32 AF XY: 0.0146 AC XY: 1089 AN XY: 74500

African (AFR) AF: 0.00413 AC: 172 AN: 41598

American (AMR) AF: 0.0103 AC: 158 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.0343 AC: 365 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1583 AN: 68034

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0155 Hom.: 14

Bravo AF: 0.0138

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0220 AC: 189

ExAC AF: 0.0151 AC: 1830

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0216

EpiControl AF: 0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

May 05, 2015

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.23
DANN	Benign	0.92
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.13	N
PhyloP100		-0.55
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.076		Gain of glycosylation at S716 (P = 0.0354)
MPC		0.26
ClinPred		0.0015	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228292; hg19: chr3-184070588;