rs1554434814
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000083.3(CLCN1):āc.547T>Cā(p.Ser183Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Consequence
CLCN1
NM_000083.3 missense
NM_000083.3 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 2.04
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.872
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.547T>C | p.Ser183Pro | missense_variant | 4/23 | ENST00000343257.7 | NP_000074.3 | |
CLCN1 | NR_046453.2 | n.649T>C | non_coding_transcript_exon_variant | 4/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.547T>C | p.Ser183Pro | missense_variant | 4/23 | 1 | NM_000083.3 | ENSP00000339867.2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151880Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 33
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151880Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74162
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 15, 2016 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2020 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function. This variant has been observed in individual(s) with autosomal dominant myotonia congenita (PMID: 23113340). ClinVar contains an entry for this variant (Variation ID: 447068). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 183 of the CLCN1 protein (p.Ser183Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. 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. - |
Congenital myotonia, autosomal dominant form Uncertain:1
Uncertain significance, no assertion criteria provided | research | Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences | Apr 06, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D
REVEL
Pathogenic
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
0.085
.;B
Vest4
0.93
MutPred
Loss of disorder (P = 0.1799);Loss of disorder (P = 0.1799);
MVP
0.94
MPC
0.34
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at