chr20-63355996-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The ENST00000370263.9(CHRNA4):c.362C>T(p.Pro121Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,800 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P121P) has been classified as Likely benign.
Frequency
Consequence
ENST00000370263.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.362C>T | p.Pro121Leu | missense_variant | 4/6 | ENST00000370263.9 | NP_000735.1 | |
CHRNA4 | NM_001256573.2 | c.-185C>T | 5_prime_UTR_variant | 4/6 | NP_001243502.1 | |||
CHRNA4 | NR_046317.2 | n.571C>T | non_coding_transcript_exon_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNA4 | ENST00000370263.9 | c.362C>T | p.Pro121Leu | missense_variant | 4/6 | 1 | NM_000744.7 | ENSP00000359285 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151290Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460510Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726556
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151290Hom.: 0 Cov.: 30 AF XY: 0.0000271 AC XY: 2AN XY: 73846
ClinVar
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 26, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 121 of the CHRNA4 protein (p.Pro121Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 581212). This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This variant is present in population databases (rs377114983, gnomAD 0.03%). - |
CHRNA4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2023 | The CHRNA4 c.362C>T variant is predicted to result in the amino acid substitution p.Pro121Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-61987348-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2020 | The p.P121L variant (also known as c.362C>T), located in coding exon 4 of the CHRNA4 gene, results from a C to T substitution at nucleotide position 362. The proline at codon 121 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at