rs563864511
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000083.3(CLCN1):āc.1060A>Gā(p.Ile354Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,984 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I354S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000083.3 missense
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 | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1060A>G | p.Ile354Val | missense_variant | 9/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1165A>G | non_coding_transcript_exon_variant | 9/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1060A>G | p.Ile354Val | missense_variant | 9/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*345A>G | 3_prime_UTR_variant, NMD_transcript_variant | 9/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1060A>G | p.Ile354Val | missense_variant | 9/23 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251474Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.00000686 AC: 10AN: 1456724Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5AN XY: 725090
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74448
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 | Invitae | Aug 31, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the CLCN1 protein (p.Ile354Val). This variant is present in population databases (rs563864511, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 568351). 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