rs185031797

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_000083.3(CLCN1):c.139C>T(p.Arg47Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,610,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R47Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.03

Publications

12 publications found

Variant links:

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CLCN1 Gene-Disease associations (from GenCC):

myotonia congenita, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
myotonia congenita, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Thomsen and Becker disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.005937189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.139C>T	p.Arg47Trp	missense_variant	Exon 1 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 link	n.241C>T		non_coding_transcript_exon_variant	Exon 1 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 link	c.139C>T	p.Arg47Trp	missense_variant	Exon 1 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000650516.2 link	c.139C>T	p.Arg47Trp	missense_variant	Exon 1 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes

AF:

0.000231

AC:

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00621

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000497

AC:

120

AN:

241654

AF XY:

0.000525

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00584

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1458718

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

725732

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00469

AC:

186

AN:

39698

South Asian (SAS)

AF:

0.000267

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111850

Other (OTH)

AF:

0.000315

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000230

AC:

AN:

151950

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00622

AC:

AN:

5144

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67950

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000101

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000429

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 23, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 15, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myotonia, autosomal dominant form

Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myotonia, autosomal recessive form

Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.0

.;L

PhyloP100

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;T

Vest4

0.0

ClinPred

0.086

GERP RS

2.2

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.086

gMVP

0.46

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over