rs201654194
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PP3_ModerateBP6_ModerateBS1BS2
The NM_000744.7(CHRNA4):c.880G>A(p.Glu294Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,613,722 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 Likely benign (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
CHRNA4
NM_000744.7 missense
NM_000744.7 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 5.94
Genes affected
CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.871
BP6
?
Variant 20-63350531-C-T is Benign according to our data. Variant chr20-63350531-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 543533.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000397 (58/1461748) while in subpopulation NFE AF= 0.0000513 (57/1112008). AF 95% confidence interval is 0.00004. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 99. This position pass quality control queck.
BS2
?
High AC in GnomAdExome4 at 58 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.880G>A | p.Glu294Lys | missense_variant | 5/6 | ENST00000370263.9 | |
CHRNA4 | NM_001256573.2 | c.352G>A | p.Glu118Lys | missense_variant | 5/6 | ||
CHRNA4 | NR_046317.2 | n.1089G>A | non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA4 | ENST00000370263.9 | c.880G>A | p.Glu294Lys | missense_variant | 5/6 | 1 | NM_000744.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151974Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251022Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135834
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GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461748Hom.: 0 Cov.: 99 AF XY: 0.0000385 AC XY: 28AN XY: 727144
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151974Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74218
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Gain of methylation at E294 (P = 0.0223);.;
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