rs759188441
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000083.3(CLCN1):c.264G>A(p.Val88=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 1 hom. )
Consequence
CLCN1
NM_000083.3 synonymous
NM_000083.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.761
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 Likely_pathogenic. Variant got 8 ACMG points.
PP5
?
Variant 7-143319838-G-A is Pathogenic according to our data. Variant chr7-143319838-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 462840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143319838-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.264G>A | p.Val88= | synonymous_variant | 2/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.366G>A | non_coding_transcript_exon_variant | 2/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.264G>A | p.Val88= | synonymous_variant | 2/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.33G>A | p.Val11= | synonymous_variant, NMD_transcript_variant | 1/23 | 1 | |||
CLCN1 | ENST00000650516.2 | c.264G>A | p.Val88= | synonymous_variant | 2/23 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251408Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135878
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461580Hom.: 1 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 727118
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74326
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change affects codon 88 of the CLCN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs759188441, gnomAD 0.08%). This variant has been observed in individuals with autosomal recessive myotonia congenita (PMID: 23152584; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 462840). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Congenital myotonia, autosomal recessive form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2024 | Variant summary: CLCN1 c.264G>A alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, sequenced mRNA of patients homozygous for the variant was shown to result in exon 2 skipping (e.g. Raheem_2012). The variant allele was found at a frequency of 8e-05 in 251408 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (8e-05 vs 0.0035), allowing no conclusion about variant significance. c.264G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with nondystrophic myotonia (e.g. Raheem_2012). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 23152584). ClinVar contains an entry for this variant (Variation ID: 462840). Based on the evidence outlined above, the variant was classified as pathogenic. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
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DS_DL_spliceai
Position offset: 37
Find out detailed SpliceAI scores and Pangolin per-transcript scores at