rs200644872
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2
The NM_000744.7(CHRNA4):c.1757C>T(p.Ser586Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,612,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S586S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000744.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.1757C>T | p.Ser586Leu | missense_variant, splice_region_variant | 5/6 | ENST00000370263.9 | |
CHRNA4 | NM_001256573.2 | c.1229C>T | p.Ser410Leu | missense_variant, splice_region_variant | 5/6 | ||
CHRNA4 | NR_046317.2 | n.1966C>T | splice_region_variant, non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA4 | ENST00000370263.9 | c.1757C>T | p.Ser586Leu | missense_variant, splice_region_variant | 5/6 | 1 | NM_000744.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247926Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134706
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1460402Hom.: 0 Cov.: 34 AF XY: 0.0000482 AC XY: 35AN XY: 726526
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152240Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74378
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2016 | A variant of uncertain significance has been identified in the CHRNA4 gene. The S586L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S586L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S586L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this amino acid substitution is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | CHRNA4: PM2:Supporting - |
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at