rs201714423
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000083.3(CLCN1):c.1129C>T(p.Arg377Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000136 in 1,614,040 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
CLCN1
NM_000083.3 stop_gained
NM_000083.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.76
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 7-143331615-C-T is Pathogenic according to our data. Variant chr7-143331615-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 447045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143331615-C-T is described in Lovd as [Pathogenic]. Variant chr7-143331615-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1129C>T | p.Arg377Ter | stop_gained | 10/23 | ENST00000343257.7 | NP_000074.3 | |
CLCN1 | NR_046453.2 | n.1234C>T | non_coding_transcript_exon_variant | 10/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1129C>T | p.Arg377Ter | stop_gained | 10/23 | 1 | NM_000083.3 | ENSP00000339867 | P4 | |
CLCN1 | ENST00000432192.6 | c.*414C>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/23 | 1 | ENSP00000395949 | ||||
CLCN1 | ENST00000650516.2 | c.1129C>T | p.Arg377Ter | stop_gained | 10/23 | ENSP00000498052 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135902
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727190
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74456
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | Reported in association with autosomal recessive myotonia congenita in the published literature (PMID: 28325641, 17932099); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 34938096, 32721234, 17932099, 23893571, 25525159, 31069529, 34529042, 28325641) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 02, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 31, 2016 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2023 | This sequence change creates a premature translational stop signal (p.Arg377*) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs201714423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 21221019). ClinVar contains an entry for this variant (Variation ID: 447045). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
CLCN1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 16, 2023 | The CLCN1 c.1129C>T variant is predicted to result in premature protein termination (p.Arg377*). This variant has been reported in the homozygous or compound heterozygous states in three patients with myotonia congenita (Fialho et al 2007. PubMed ID: 17932099; Modoni et al 2011. PubMed ID: 21221019), and in one patient with myotonia congenita in which a second potentially pathogenic variant was not identified (Sun et al 2020. PubMed ID: 31567646). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143028708-C-T). Nonsense variants in CLCN1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 37
Find out detailed SpliceAI scores and Pangolin per-transcript scores at