Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM4_SupportingBP6

The NM_000083.3(CLCN1):c.2062_2063insTTC(p.Gly688delinsValArg) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000053 in 1,565,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.84

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000083.3. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 7-143345652-G-GTTC is Benign according to our data. Variant chr7-143345652-G-GTTC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422404.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.2062_2063insTTC	p.Gly688delinsValArg	disruptive_inframe_insertion	Exon 17 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.2017_2018insTTC		non_coding_transcript_exon	Exon 16 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.2062_2063insTTC	p.Gly688delinsValArg	disruptive_inframe_insertion	Exon 17 of 23	ENSP00000339867.2
CLCN1	ENST00000432192.6	TSL:1	n.1347_1348insTTC		non_coding_transcript_exon	Exon 17 of 23	ENSP00000395949.2
CLCN1	ENST00000432192.6	TSL:1	n.1347_1348insTTC		3_prime_UTR	Exon 17 of 23	ENSP00000395949.2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000146

AC:

AN:

170760

AF XY:

0.000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000380

Gnomad ASJ exome

AF:

0.00267

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1413386

Hom.:

Cov.:

AF XY:

0.0000458

AC XY:

AN XY:

698704

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32386

American (AMR)

AF:

0.0000267

AC:

AN:

37414

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

25286

East Asian (EAS)

AF:

0.00

AC:

AN:

36950

South Asian (SAS)

AF:

0.00

AC:

AN:

80406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.00000919

AC:

AN:

1087810

Other (OTH)

AF:

0.0000684

AC:

AN:

58490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000788

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.000391

Hom.:

Bravo

AF:

0.0000982

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Splicing

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.

rs770836890

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over