rs201864944
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000744.7(CHRNA4):c.1537C>T(p.Arg513Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,593,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R513H) has been classified as Likely benign.
Frequency
Consequence
NM_000744.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.1537C>T | p.Arg513Cys | missense_variant | 5/6 | ENST00000370263.9 | |
CHRNA4 | NM_001256573.2 | c.1009C>T | p.Arg337Cys | missense_variant | 5/6 | ||
CHRNA4 | NR_046317.2 | n.1746C>T | non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA4 | ENST00000370263.9 | c.1537C>T | p.Arg513Cys | missense_variant | 5/6 | 1 | NM_000744.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000218 AC: 5AN: 229486Hom.: 0 AF XY: 0.0000240 AC XY: 3AN XY: 124772
GnomAD4 exome AF: 0.0000111 AC: 16AN: 1441688Hom.: 0 Cov.: 82 AF XY: 0.0000126 AC XY: 9AN XY: 714260
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 513 of the CHRNA4 protein (p.Arg513Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 577644). 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 not expected to disrupt CHRNA4 protein function with a negative predictive value of 80%. 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