rs142539932
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_000083.3(CLCN1):c.2926C>T(p.Arg976Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,613,610 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 1 hom. )
Consequence
CLCN1
NM_000083.3 stop_gained
NM_000083.3 stop_gained
Scores
1
3
3
Clinical Significance
Conservation
PhyloP100: 2.27
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 Uncertain_significance. Variant got 2 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. Fraction of 0.0138 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.2926C>T | p.Arg976Ter | stop_gained | 23/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.2881C>T | non_coding_transcript_exon_variant | 22/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.2926C>T | p.Arg976Ter | stop_gained | 23/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000650516.2 | c.2926C>T | p.Arg976Ter | stop_gained | 23/23 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000651 AC: 99AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000279 AC: 70AN: 251056Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135772
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GnomAD4 exome AF: 0.000162 AC: 237AN: 1461356Hom.: 1 Cov.: 32 AF XY: 0.000160 AC XY: 116AN XY: 726996
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | literature only | OMIM | Mar 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2021 | Observed with a second variant in a family with myotonia congenita in published literature, however it is not known whether these variants are on the same allele (in cis) or on different alleles (in trans) (Modoni et al., 2011); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 20301529, 25964741, 23408874, 25012387, 21221019, 23739125, 26471370, 25088311, 25065301, 32010054, 27535533) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 15, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: CLCN1 c.2926C>T (p.Arg976X) results in a premature termination codon, predicted to cause a truncation of the encoded protein by removing the last 13 amino acids. No pathogenic variants have been observed downstream. The variant allele was found at a frequency of 0.00021 in 1613610 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (0.00021 vs 0.0035), allowing no conclusion about variant significance. c.2926C>T has been reported in the literature in individuals affected with Myotonia congenita (Suetterlin_2022, Modoni_2011, Vereb_2021) without definitive evidence for causality. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21221019, 34529042, 33263785). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change creates a premature translational stop signal (p.Arg976*) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acid(s) of the CLCN1 protein. This variant is present in population databases (rs142539932, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive myotonia congenita (PMID: 21221019, 33263785). ClinVar contains an entry for this variant (Variation ID: 199652). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Batten-Turner congenital myopathy Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at