rs755176513
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_000083.3(CLCN1):c.2831dup(p.Gly945ArgfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
CLCN1
NM_000083.3 frameshift
NM_000083.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.04
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 10 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 0.0472 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PP5
Variant 7-143351825-G-GC is Pathogenic according to our data. Variant chr7-143351825-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.2831dup | p.Gly945ArgfsTer39 | frameshift_variant | 23/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.2786dup | non_coding_transcript_exon_variant | 22/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.2831dup | p.Gly945ArgfsTer39 | frameshift_variant | 23/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000650516.2 | c.2831dup | p.Gly945ArgfsTer39 | frameshift_variant | 23/23 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250568Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135536
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461726Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727126
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74434
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
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 | Jun 09, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is expected to result in a shift of the reading frame and a premature stop codon. Since this variant is located in the last exon of the gene, variant-containing transcripts likely escape nonsense-mediated decay. This variant has been reported in multiple families with autosomal recessive myotonia congenita in published literature and internal data (PMID: 18337100, Athena Diagnostics internal data). This variant is also referred to as 2828insC in published literature. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2018 | The c.2831dupC likely pathogenic variant in the CLCN1 gene has been reported previously as c.2828insC due to alternative nomenclature, in an individual with severe myotonia, tongue myotonia, and lid myotonia, who also harbored a second CLCN1 pathogenic variant, suggestive of autosomal recessive inheritance (Dupree et al., 2009). The duplication causes a frameshift starting with codon Glycine 945, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Gly945ArgfsX39. This likely pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 44 amino acid residues are replaced with 38 incorrect amino acid residues. The c.2831dupC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 27, 2022 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change creates a premature translational stop signal (p.Gly945Argfs*39) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the CLCN1 protein. This variant is present in population databases (rs755176513, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 18337100; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2828insC. ClinVar contains an entry for this variant (Variation ID: 280103). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at