rs2228292

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.547

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 217778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184352800-C-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN2	NM_004366.6 linkuse as main transcript	c.2154G>C	p.Glu718Asp	missense_variant	19/24	ENST00000265593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN2	ENST00000265593.9 linkuse as main transcript	c.2154G>C	p.Glu718Asp	missense_variant	19/24	1	NM_004366.6	P1	P51788-1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2343

AN:

152252

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0150

AC:

3754

AN:

249834

Hom.:

AF XY:

0.0152

AC XY:

2065

AN XY:

135486

show subpopulations

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 SAS exome

AF:

0.00291

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.:

AF XY:

0.0211

AC XY:

15337

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.00338

Gnomad4 AMR exome

AF:

0.00617

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00268

Gnomad4 FIN exome

AF:

0.0328

Gnomad4 NFE exome

AF:

0.0254

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0154

AC:

2344

AN:

152370

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1089

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00413

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0343

Gnomad4 NFE

AF:

0.0233

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0151

AC:

1830

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 05, 2015

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

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

LIST_S2

Benign

0.80

T;T;T;T

MetaRNN

Benign

0.0046

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.13

N;.;.;N

MutationTaster

Benign

0.97

N;N;N;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.020

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.34

T;T;T;T

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.14

MutPred

0.076

Gain of glycosylation at S716 (P = 0.0354);.;.;Gain of glycosylation at S716 (P = 0.0354);

MPC

0.26

ClinPred

0.0015

GERP RS

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.32

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over