rs913563840
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000742.4(CHRNA2):c.322A>G(p.Asn108Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,984 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N108T) has been classified as Likely benign.
Frequency
Consequence
NM_000742.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA2 | NM_000742.4 | c.322A>G | p.Asn108Asp | missense_variant | 4/7 | ENST00000407991.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA2 | ENST00000407991.3 | c.322A>G | p.Asn108Asp | missense_variant | 4/7 | 5 | NM_000742.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151984Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1404784Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 693388
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74232
ClinVar
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2017 | Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with CHRNA2-related disease. ClinVar contains an entry for this variant (Variation ID: 421445). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 108 of the CHRNA2 protein (p.Asn108Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2016 | A variant of uncertain significance has been identified in the CHRNA2 gene. The N108D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N108D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at