rs774407731
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000080.4(CHRNE):āc.820A>Gā(p.Thr274Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. T274T) has been classified as Likely benign.
Frequency
Consequence
NM_000080.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNE | NM_000080.4 | c.820A>G | p.Thr274Ala | missense_variant | 8/12 | ENST00000649488.2 | |
C17orf107 | NM_001145536.2 | c.*357T>C | 3_prime_UTR_variant | 3/3 | ENST00000381365.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNE | ENST00000649488.2 | c.820A>G | p.Thr274Ala | missense_variant | 8/12 | NM_000080.4 | P1 | ||
C17orf107 | ENST00000381365.4 | c.*357T>C | 3_prime_UTR_variant | 3/3 | 2 | NM_001145536.2 | A2 | ||
CHRNE | ENST00000649830.1 | c.-114A>G | 5_prime_UTR_variant | 8/11 | |||||
CHRNE | ENST00000572438.1 | n.506A>G | non_coding_transcript_exon_variant | 3/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000679 AC: 17AN: 250216Hom.: 0 AF XY: 0.0000886 AC XY: 12AN XY: 135462
GnomAD4 exome AF: 0.000125 AC: 182AN: 1461816Hom.: 1 Cov.: 34 AF XY: 0.000116 AC XY: 84AN XY: 727224
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Congenital myasthenic syndrome 4A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2022 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 274 of the CHRNE protein (p.Thr274Ala). This variant is present in population databases (rs774407731, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 323988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNE protein function. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2023 | The c.820A>G (p.T274A) alteration is located in exon 8 (coding exon 8) of the CHRNE gene. This alteration results from a A to G substitution at nucleotide position 820, causing the threonine (T) at amino acid position 274 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at