NM_000083.3:c.2244G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000083.3(CLCN1):c.2244G>A(p.Leu748Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,444 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L748L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 43 hom., cov: 31)

Exomes 𝑓: 0.013 ( 175 hom. )

Consequence

CLCN1
NM_000083.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.89

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 7-143346211-G-A is Benign according to our data. Variant chr7-143346211-G-A is described in ClinVar as Benign. ClinVar VariationId is 359122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0171 (2608/152086) while in subpopulation AFR AF = 0.0306 (1269/41460). AF 95% confidence interval is 0.0292. There are 43 homozygotes in GnomAd4. There are 1215 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 43 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.2244G>A	p.Leu748Leu	synonymous	Exon 18 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.2199G>A		non_coding_transcript_exon	Exon 17 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.2244G>A	p.Leu748Leu	synonymous	Exon 18 of 23	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6	TSL:1	n.*1529G>A		non_coding_transcript_exon	Exon 18 of 23	ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6	TSL:1	n.*1529G>A		3_prime_UTR	Exon 18 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2607

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.0554

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00444

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0130

AC:

3258

AN:

251308

AF XY:

0.0127

show subpopulations

Gnomad AFR exome

AF:

0.0308

Gnomad AMR exome

AF:

0.00888

Gnomad ASJ exome

AF:

0.0524

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0131

AC:

19081

AN:

1461358

Hom.:

175

Cov.:

AF XY:

0.0128

AC XY:

9338

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.0325

AC:

1089

AN:

33466

American (AMR)

AF:

0.00993

AC:

444

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0500

AC:

1307

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00678

AC:

585

AN:

86254

European-Finnish (FIN)

AF:

0.00465

AC:

248

AN:

53378

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0129

AC:

14385

AN:

1111572

Other (OTH)

AF:

0.0159

AC:

962

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

915

1830

2746

3661

4576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.0171

AC:

2608

AN:

152086

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0306

AC:

1269

AN:

41460

American (AMR)

AF:

0.0133

AC:

204

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0554

AC:

192

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00601

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00444

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0120

AC:

817

AN:

68008

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

136

272

408

544

680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0143

Hom.:

Bravo

AF:

0.0197

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0151

EpiControl

AF:

0.0162

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Batten-Turner congenital myopathy (1)

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.1

(source)

DANN

Benign

0.79

PhyloP100

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over