chr7-143331582-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3
The NM_000083.3(CLCN1):c.1096G>T(p.Val366Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,826 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V366A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000083.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1096G>T | p.Val366Leu | missense_variant | 10/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1201G>T | non_coding_transcript_exon_variant | 10/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1096G>T | p.Val366Leu | missense_variant | 10/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*381G>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1096G>T | p.Val366Leu | missense_variant | 10/23 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727212
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 25, 2017 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 366 of the CLCN1 protein (p.Val366Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myotonia congenita (Invitae). ClinVar contains an entry for this variant (Variation ID: 447044). 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. 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