dbSNP rs118066140: CLCN1:p.Arg300Gln (chr7-143330817-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1PP2PP3BP4_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

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 -5 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000083.3

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.

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 VariationId is 252463.

BS2

High Homozygotes in GnomAdExome4 at 45 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.899G>A	p.Arg300Gln	missense	Exon 8 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.1004G>A		non_coding_transcript_exon	Exon 8 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.899G>A	p.Arg300Gln	missense	Exon 8 of 23	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6	TSL:1	n.*184G>A		non_coding_transcript_exon	Exon 8 of 23	ENSP00000395949.2	H7C0N6
CLCN1	ENST00000455478.6	TSL:1	n.*184G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000400027.2	H7C1F4

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

African (AFR)

AF:

0.00105

AC:

AN:

33480

American (AMR)

AF:

0.00235

AC:

105

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000880

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00512

AC:

442

AN:

86256

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00871

AC:

9691

AN:

1112002

Other (OTH)

AF:

0.00527

AC:

318

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

656

1312

1969

2625

3281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00166

AC:

AN:

41550

American (AMR)

AF:

0.00288

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00783

AC:

533

AN:

68038

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

112

149

186

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:

0.00647

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (2)

Batten-Turner congenital myopathy (1)

Congenital myotonia, autosomal recessive form (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.0053

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.9

PhyloP100

8.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

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)

(source)

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

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