rs547603982
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The ENST00000343257.7(CLCN1):c.1168C>T(p.Arg390Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000062 in 1,613,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390H) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000343257.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1168C>T | p.Arg390Cys | missense_variant, splice_region_variant | 11/23 | ENST00000343257.7 | NP_000074.3 | |
CLCN1 | NR_046453.2 | n.1273C>T | splice_region_variant, non_coding_transcript_exon_variant | 11/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1168C>T | p.Arg390Cys | missense_variant, splice_region_variant | 11/23 | 1 | NM_000083.3 | ENSP00000339867 | P4 | |
CLCN1 | ENST00000432192.6 | c.*453C>T | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 11/23 | 1 | ENSP00000395949 | ||||
CLCN1 | ENST00000650516.2 | c.1168C>T | p.Arg390Cys | missense_variant, splice_region_variant | 11/23 | ENSP00000498052 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251456Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461222Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726986
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74442
ClinVar
Submissions by phenotype
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 | Aug 30, 2021 | This sequence change replaces arginine with cysteine at codon 390 of the CLCN1 protein (p.Arg390Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs547603982, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at