3-184353722-C-A

Variant names:

• chr3-184353722-C-A
• rs141242566
• NM_004366.6:c.1795G>T

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.1795G>T​(p.Asp599Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,457,348 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. D599N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02
• Publications: 12 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, 0.896

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.1795G>T	p.Asp599Tyr	missense	Exon 16 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.1744G>T	p.Asp582Tyr	missense	Exon 16 of 24	NP_001164558.1	P51788-3
	CLCN2	NM_001171089.3		c.1795G>T	p.Asp599Tyr	missense	Exon 16 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.1795G>T	p.Asp599Tyr	missense	Exon 16 of 24	ENSP00000265593.4	P51788-1
	CLCN2	ENST00000344937.11	TSL:1	c.1744G>T	p.Asp582Tyr	missense	Exon 16 of 24	ENSP00000345056.7	P51788-3
	CLCN2	ENST00000430397.5	TSL:1	n.*261G>T		non_coding_transcript_exon	Exon 6 of 13	ENSP00000396231.1	H7C0Q8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 240662 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457348 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 724520

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110408

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000489 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.54		Gain of MoRF binding (P = 0.05)
MVP		0.95
MPC		1.0
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.85
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs141242566; hg19: chr3-184071510;