rs1057518917

Positions:

chr7-143351633-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.2635C>T(p.Gln879Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.41

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 made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.

PP5

Variant 7-143351633-C-T is Pathogenic according to our data. Variant chr7-143351633-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143351633-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2635C>T	p.Gln879Ter	stop_gained	23/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.2590C>T		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2635C>T	p.Gln879Ter	stop_gained	23/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*1920C>T		3_prime_UTR_variant, NMD_transcript_variant	23/23	1
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2635C>T	p.Gln879Ter	stop_gained	23/23			A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248664

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134706

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2021	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in individuals with apparently recessive myotonia congenita (PMID: 23739125, 23113340). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to cause a complete loss of chloride ion flow through the ClC1 channel (PMID: 16321142). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2023	Reported previously in an individual with myotonia congenita who harbored a second benign variant in the CLCL1 gene, suggesting autosomal dominant inheritance (Brugnoni et al., 2013); Functional studies indicate that this variant destroys skeletal-muscle chloride channel function as no chloride currents were elicited from Xenopus oocytes containing Q879X (Wu et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 110 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 16321142, 23739125, 23113340, 34106991) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 18, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLCN1 protein in which other variant(s) (p.Gly945Argfs*39) have been determined to be pathogenic (PMID: 18337100; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 374131). This sequence change creates a premature translational stop signal (p.Gln879*) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the CLCN1 protein. This variant is present in population databases (no rsID available, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with myotonia congenita (PMID: 23113340, 23739125). -

Myotonia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 23, 2015

- -

Congenital myotonia, autosomal dominant form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 07, 2022

- -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

MutationTaster

Benign

1.0

Vest4

0.72

GERP RS

3.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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