3-184358977-C-T

Position:

chr3-184358977-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/23 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).

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

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 -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 id is 217770.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, not_provided=1}. Variant chr3-184358977-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.218G>A	p.Arg73His	missense_variant, splice_region_variant	2/24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 link	c.218G>A	p.Arg73His	missense_variant, splice_region_variant	2/24	1	NM_004366.6	ENSP00000265593.4		P51788-1

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

GnomAD3 exomes

AF:

0.00244

AC:

611

AN:

250490

Hom.:

AF XY:

0.00249

AC XY:

338

AN XY:

135612

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 SAS exome

AF:

0.00203

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

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.00907

Gnomad4 NFE exome

AF:

0.00202

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00200

AC:

305

AN:

152332

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

165

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00165

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.00260

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00196

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CLCN2: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 13, 2017

- -

CLCN2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;.;.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.85

D;D;T;D;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0080

T;T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.3

L;L;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

N;N;N;N;.

REVEL

Uncertain

0.48

Sift

Benign

0.17

T;T;D;T;.

Sift4G

Benign

0.14

T;T;D;T;.

Polyphen

0.0020

B;B;.;.;.

Vest4

0.74

MVP

0.80

MPC

0.36

ClinPred

0.023

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.41

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

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