NM_004366.6:c.596G>C

Variant names:

• chr3-184357981-C-G
• rs863225248
• NM_004366.6:c.596G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004366.6(CLCN2):​c.596G>C​(p.Gly199Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G199R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.16
• Publications: 2 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, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	NM_004366.6	MANE Select	c.596G>C	p.Gly199Ala	missense	Exon 5 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.596G>C	p.Gly199Ala	missense	Exon 5 of 24	NP_001164558.1	P51788-3
	CLCN2	NM_001171089.3		c.596G>C	p.Gly199Ala	missense	Exon 5 of 23	NP_001164560.1	P51788-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.596G>C	p.Gly199Ala	missense	Exon 5 of 24	ENSP00000265593.4	P51788-1
	CLCN2	ENST00000344937.11	TSL:1	c.596G>C	p.Gly199Ala	missense	Exon 5 of 24	ENSP00000345056.7	P51788-3
	CLCN2	ENST00000938001.1		c.713G>C	p.Gly238Ala	missense	Exon 6 of 25	ENSP00000608060.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hyperaldosteronism type II;C2750893:Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)
-	-	-	Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.70		Loss of glycosylation at S198 (P = 0.0217)
MVP		0.98
MPC		0.92
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.83
gMVP		0.92
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs863225248; hg19: chr3-184075769;