7-143330817-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 6P and 9B. PM1PM5PP2PP3BP4_StrongBP6BS2

The NM_000083.3(CLCN1):c.899G>A(p.Arg300Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,162 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts 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. R300W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 45 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 8.13

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000083.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143330816-C-T is described in Lovd as [Pathogenic].

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 Thomsen and Becker disease, myotonia congenita, autosomal recessive, myotonia congenita, autosomal dominant.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when AlphaMissense, BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.016606092).

BP6

Variant 7-143330817-G-A is Benign according to our data. Variant chr7-143330817-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252463.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=6}. Variant chr7-143330817-G-A is described in Lovd as [Pathogenic]. Variant chr7-143330817-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.899G>A	p.Arg300Gln	missense_variant	Exon 8 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1004G>A		non_coding_transcript_exon_variant	Exon 8 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 link	c.899G>A	p.Arg300Gln	missense_variant	Exon 8 of 23	1	NM_000083.3	ENSP00000339867.2		P35523

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

698

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00783

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00475

AC:

1195

AN:

251402

AF XY:

0.00498

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00785

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00734

AC:

10728

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

5303

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00235

AC:

105

AN:

44724

Gnomad4 ASJ exome

AF:

0.000880

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.000176

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00512

AC:

442

AN:

86256

Gnomad4 FIN exome

AF:

0.00180

AC:

AN:

53416

Gnomad4 NFE exome

AF:

0.00871

AC:

9691

AN:

1112002

Gnomad4 Remaining exome

AF:

0.00527

AC:

318

AN:

60396

Heterozygous variant carriers

656

1312

1969

2625

3281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.00458

AC:

698

AN:

152286

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00166

AC:

0.00166065

AN:

0.00166065

Gnomad4 AMR

AF:

0.00288

AC:

0.00287695

AN:

0.00287695

Gnomad4 ASJ

AF:

0.000576

AC:

0.000576369

AN:

0.000576369

Gnomad4 EAS

AF:

0.000386

AC:

0.000385802

AN:

0.000385802

Gnomad4 SAS

AF:

0.00622

AC:

0.00622407

AN:

0.00622407

Gnomad4 FIN

AF:

0.00122

AC:

0.0012248

AN:

0.0012248

Gnomad4 NFE

AF:

0.00783

AC:

0.00783386

AN:

0.00783386

Gnomad4 OTH

AF:

0.00190

AC:

0.00189573

AN:

0.00189573

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00647

Hom.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00464

AC:

564

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00848

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 25, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it 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 disease. -

Nov 06, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLCN1: PP3, BS2 -

Feb 16, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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.899G>A (p.(Arg300Gln)) variant was found in a heterozygous state in 2 Slovak patients with Myotonia congenita: the first one carried another 2 Likely Pathogenic variants: c.1231G>T and C2680C>T; while in the second one, no other Pathogenic or Likely pathogenic variants were found. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.00734. This variant has been reported in HGMD database CM940284. -

Congenital myotonia, autosomal recessive form

Uncertain:1

Sep 21, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Batten-Turner congenital myopathy

Benign:1

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.0053

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.9

.;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

.;D

Polyphen

1.0

.;D

Vest4

0.79

MVP

0.98

MPC

0.68

ClinPred

0.023

GERP RS

3.7

Varity_R

0.92

gMVP

0.77

Mutation Taster

=78/22

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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