rs281865067
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP3PP5
The NM_000744.7(CHRNA4):c.872_873insGCT(p.Leu290dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L291L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CHRNA4
NM_000744.7 inframe_insertion
NM_000744.7 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.03
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a helix (size 18) in uniprot entity ACHA4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000744.7
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000744.7. Strenght limited to Supporting due to length of the change: 1aa.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 20-63350538-G-GAGC is Pathogenic according to our data. Variant chr20-63350538-G-GAGC is described in ClinVar as [Pathogenic]. Clinvar id is 41030.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.872_873insGCT | p.Leu290dup | inframe_insertion | 5/6 | ENST00000370263.9 | |
CHRNA4 | NM_001256573.2 | c.344_345insGCT | p.Leu114dup | inframe_insertion | 5/6 | ||
CHRNA4 | NR_046317.2 | n.1081_1082insGCT | non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA4 | ENST00000370263.9 | c.872_873insGCT | p.Leu290dup | inframe_insertion | 5/6 | 1 | NM_000744.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 99
GnomAD4 exome
Cov.:
99
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy 1 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 10, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at