Genetic Variant CLCN2:p.Arg73His (chr3-184358977-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004366.6(CLCN2):c.218G>A(p.Arg73His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,514 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 10 hom. )

Consequence

CLCN2
NM_004366.6 missense, splice_region

Scores

Splicing: ADA: 0.0001276

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: -0.337

Publications

9 publications found

Variant links:

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

CLCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009835452).

BP6

Variant 3-184358977-C-T is Benign according to our data. Variant chr3-184358977-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217770.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (305/152332) while in subpopulation NFE AF = 0.0026 (177/68032). AF 95% confidence interval is 0.00229. There are 1 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN2	NM_004366.6	MANE Select	c.218G>A	p.Arg73His	missense splice_region	Exon 2 of 24	NP_004357.3
CLCN2	NM_001171087.3		c.218G>A	p.Arg73His	missense splice_region	Exon 2 of 24	NP_001164558.1	P51788-3
CLCN2	NM_001171089.3		c.218G>A	p.Arg73His	missense splice_region	Exon 2 of 23	NP_001164560.1	P51788-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.218G>A	p.Arg73His	missense splice_region	Exon 2 of 24	ENSP00000265593.4	P51788-1
CLCN2	ENST00000344937.11	TSL:1	c.218G>A	p.Arg73His	missense splice_region	Exon 2 of 24	ENSP00000345056.7	P51788-3
CLCN2	ENST00000938001.1		c.335G>A	p.Arg112His	missense splice_region	Exon 3 of 25	ENSP00000608060.1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00244

AC:

611

AN:

250490

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00994

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00210

AC:

3066

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

1571

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000850

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00192

AC:

166

AN:

86258

European-Finnish (FIN)

AF:

0.00907

AC:

479

AN:

52788

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00202

AC:

2244

AN:

1111956

Other (OTH)

AF:

0.00161

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00200

AC:

305

AN:

152332

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

165

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41566

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00165

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00904

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00260

AC:

177

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00262

AC:

318

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CLCN2-related disorder (1)

Leukoencephalopathy with mild cerebellar ataxia and white matter edema (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.3

PhyloP100

-0.34

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.48

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.0020

Vest4

0.74

MVP

0.80

MPC

0.36

ClinPred

0.023

GERP RS

3.7

PromoterAI

0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.41

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.016

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over