rs137852681

Variant names:

• chr3-184352810-C-T
• rs137852681
• NM_004366.6:c.2144G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_004366.6(CLCN2):​c.2144G>A​(p.Gly715Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLCN2 NM_004366.6 missense, splice_region
• Scores: Splicing: ADA: 0.9968
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 1.98
• 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, 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2144G>A	p.Gly715Glu	missense splice_region	Exon 19 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.2093G>A	p.Gly698Glu	missense splice_region	Exon 19 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.2144G>A	p.Gly715Glu	missense splice_region	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.2144G>A	p.Gly715Glu	missense splice_region	Exon 19 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.2093G>A	p.Gly698Glu	missense splice_region	Exon 19 of 24	ENSP00000345056.7
	CLCN2	ENST00000430397.5	TSL:1	n.*610G>A		splice_region non_coding_transcript_exon	Exon 9 of 13	ENSP00000396231.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249760 AF XY: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460888 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726746

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

EPILEPSY, JUVENILE ABSENCE, SUSCEPTIBILITY TO, 2 Uncertain:1

Sep 01, 2009

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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	0.11
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.013	D
Sift4G	Benign	0.10	T
Polyphen		0.87	P
Vest4		0.65
MutPred		0.19		Gain of glycosylation at S716 (P = 0.0354)
MVP		0.86
MPC		0.44
ClinPred		0.40	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.42
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
Splicevardb		2.0
SpliceAI score (max)		0.16		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: rs137852681; hg19: chr3-184070598;