rs146160029

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_000083.3(CLCN1):c.86A>C(p.His29Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00374 in 1,613,774 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 13 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.94

Publications

14 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: Benign. The variant received -15 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=0.015843928).

BP6

Variant 7-143316298-A-C is Benign according to our data. Variant chr7-143316298-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.86A>C	p.His29Pro	missense_variant	Exon 1 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 link	n.188A>C		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.86A>C	p.His29Pro	missense_variant	Exon 1 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000650516.2 link	c.86A>C	p.His29Pro	missense_variant	Exon 1 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00438

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00252

AC:

631

AN:

250872

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00456

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00389

AC:

5680

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

2776

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33476

American (AMR)

AF:

0.00157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000951

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000394

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00466

AC:

5181

AN:

1111906

Other (OTH)

AF:

0.00424

AC:

256

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

288

577

865

1154

1442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.00230

AC:

350

AN:

152134

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

41498

American (AMR)

AF:

0.000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00438

AC:

298

AN:

67988

Other (OTH)

AF:

0.00190

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00349

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00246

AC:

298

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLCN1: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24349310, 32117024) -

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

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The c.86A>C (p.(His29Pro)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita. No other Pathogenic or Likely pathogenic variants were found in this individual. This change occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with the disease. Variant c.86A>C was reported in the HGDM database (CM1313396) in cis with another disease-causing variant. It has been published in PMID: 24349310, found in a patient with AR Becker disease, who carried also two other Pathogeniec/Likely pathogenic CLCN1 variants. -

not specified

Benign:1

Nov 19, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Batten-Turner congenital myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CLCN1-related disorder

Benign:1

Jan 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.97

.;L

PhyloP100

3.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

.;N

REVEL

Pathogenic

0.81

Sift

Uncertain

0.011

.;D

Sift4G

Benign

0.072

.;T

Polyphen

0.97

.;D

Vest4

0.59

MVP

0.96

MPC

0.75

ClinPred

0.082

GERP RS

4.0

PromoterAI

0.013

Neutral

(source)

Varity_R

0.36

gMVP

0.67

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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