rs1554438441
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000083.3(CLCN1):c.1662_1663dup(p.His555LeufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A554A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CLCN1
NM_000083.3 frameshift
NM_000083.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.90
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-143342006-G-GCT is Pathogenic according to our data. Variant chr7-143342006-G-GCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523318.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1662_1663dup | p.His555LeufsTer6 | frameshift_variant | 15/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1617_1618dup | non_coding_transcript_exon_variant | 14/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1662_1663dup | p.His555LeufsTer6 | frameshift_variant | 15/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*947_*948dup | 3_prime_UTR_variant, NMD_transcript_variant | 15/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1662_1663dup | p.His555LeufsTer6 | frameshift_variant | 15/23 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypoplasia of the maxilla;C0410264:Achilles tendon contracture;C0700153:Myotonia;C1184923:Lumbar hyperlordosis;C2265792:Skeletal muscle hypertrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at