Variant chr3-184353275-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004366.6(CLCN2):c.2003C>G(p.Thr668Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,082 control chromosomes in the GnomAD database, including 229,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23661 hom., cov: 33)

Exomes 𝑓: 0.52 ( 205804 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 1.49

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:

CLCN2 (HGNC:):

CLCN2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.0687833E-6).

BP6

Variant 3-184353275-G-C is Benign according to our data. Variant chr3-184353275-G-C is described in ClinVar as [Benign]. Clinvar id is 217776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184353275-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6 linkuse as main transcript	c.2003C>G	p.Thr668Ser	missense_variant	17/24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 linkuse as main transcript	c.2003C>G	p.Thr668Ser	missense_variant	17/24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.545

AC:

82836

AN:

152014

Hom.:

23634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.431

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.0969

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.558

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.538

GnomAD3 exomes

AF:

0.473

AC:

118966

AN:

251278

Hom.:

30773

AF XY:

0.481

AC XY:

65313

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.324

Gnomad ASJ exome

AF:

0.477

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.479

Gnomad FIN exome

AF:

0.426

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.522

AC:

762052

AN:

1460948

Hom.:

205804

Cov.:

AF XY:

0.521

AC XY:

378757

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.679

Gnomad4 AMR exome

AF:

0.335

Gnomad4 ASJ exome

AF:

0.472

Gnomad4 EAS exome

AF:

0.0694

Gnomad4 SAS exome

AF:

0.474

Gnomad4 FIN exome

AF:

0.432

Gnomad4 NFE exome

AF:

0.550

Gnomad4 OTH exome

AF:

0.509

GnomAD4 genome

AF:

0.545

AC:

82902

AN:

152134

Hom.:

23661

Cov.:

AF XY:

0.530

AC XY:

39424

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.684

Gnomad4 AMR

AF:

0.431

Gnomad4 ASJ

AF:

0.459

Gnomad4 EAS

AF:

0.0967

Gnomad4 SAS

AF:

0.462

Gnomad4 FIN

AF:

0.411

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.532

Alfa

AF:

0.508

Hom.:

5541

Bravo

AF:

0.551

TwinsUK

AF:

0.541

AC:

2005

ALSPAC

AF:

0.553

AC:

2132

ESP6500AA

AF:

0.680

AC:

2994

ESP6500EA

AF:

0.550

AC:

4729

ExAC

AF:

0.489

AC:

59427

Asia WGS

AF:

0.318

AC:

1112

AN:

3478

EpiCase

AF:

0.553

EpiControl

AF:

0.559

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.3

DANN

Benign

0.65

DEOGEN2

Benign

0.070

T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.041

T;T;T;T

MetaRNN

Benign

0.0000041

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.47

N;.;.;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.92

N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.83

T;T;T;T

Sift4G

Benign

0.78

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.031

MutPred

0.23

Loss of glycosylation at P667 (P = 0.0121);.;.;Loss of glycosylation at P667 (P = 0.0121);

MPC

0.26

ClinPred

0.0018

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.23

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

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