rs776073429
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_000083.3(CLCN1):c.774+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,608,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000083.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.774+1G>A | splice_donor_variant | ENST00000343257.7 | |||
CLCN1 | NR_046453.2 | n.876+1G>A | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.774+1G>A | splice_donor_variant | 1 | NM_000083.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251426Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
GnomAD4 exome AF: 0.0000261 AC: 38AN: 1456030Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 18AN XY: 724764
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2019 | Identified, in the heterozygous and compound heterozygous state, in multiple unrelated patients with myotonia referred for testing at GeneDx and in published literature (Hehir et al., 2013; Bissay et al., 2016); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26036855, 29606556, 23417379, 21387378) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 17, 2020 | PVS1, PS4_moderate, PM2, PP1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 08, 2022 | This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in multiple individuals with apparently autosomal recessive myotonia congenita both internally and in the literature (PMID: 21387378). However, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 23417379, 26036855). Computational tools yielded predictions that this variant may interfere with normal RNA splicing. - |
Batten-Turner congenital myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The CLCN1 c.774+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across three studies this variant was identified in a total of eight individuals. Tan et al. (2011) found the c.774+1G>A variant in a compound heterozygous state with another splice variant in an individual with myotonia congenita. The c.774+1G>A variant was subsequently found in a heterozygous state in a 31 year old man with myotonia as well as his affected mother (Hehir et al. 2013). Additionally, Bissay et al. (2015) identified the variant in at least five members of a family with both Brugada syndrome and myotonic features. The c.774+1G>A variant segregated with disease within the family. Control data are unavailable from these studies but the c.774+1G>A variant is reported at a frequency of 0.00019 in the African population of the Exome Aggregation Consortium, though this frequency is based on only two alleles in a region of good sequencing coverage. Based on the evidence from the literature and the potential impact of splice donor variants, the c.774+1G>A variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change affects a donor splice site in intron 6 of the CLCN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs776073429, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with autosomal recessive myotonia congenita (PMID: 21387378, 34529042; Invitae). ClinVar contains an entry for this variant (Variation ID: 265646). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at