rs74341575
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_000742.4(CHRNA2):c.1073G>T(p.Ser358Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
CHRNA2
NM_000742.4 missense
NM_000742.4 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 4.08
Genes affected
CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3054665).
BP6
?
Variant 8-27463370-C-A is Benign according to our data. Variant chr8-27463370-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
?
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA2 | NM_000742.4 | c.1073G>T | p.Ser358Ile | missense_variant | 6/7 | ENST00000407991.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA2 | ENST00000407991.3 | c.1073G>T | p.Ser358Ile | missense_variant | 6/7 | 5 | NM_000742.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000798 AC: 20AN: 250536Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135468
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44AN XY: 727160
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74440
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2014 | p.Ser358Ile (AGC>ATC): c.1073 G>T in exon 6 of the CHRNA2 gene (NM_000742.3). The S358I missense change has not been published as a mutation, nor has it been reported as a benign polymorphism 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. This variant is a non-conservative amino acid substitution, which is is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this amino acid substitution occurs at a position that is not highly conserved across species and does not occur within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. The variant is found in INFANT-EPI panel(s). - |
Autosomal dominant nocturnal frontal lobe epilepsy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Polyphen
B;.;.
Vest4
MutPred
Loss of disorder (P = 0.0048);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at