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NM_000742.4(CHRNA2):c.1434C>A (p.Asp478Glu)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(4);Likely benign(4);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Jan 7, 2021)
Last evaluated:
Dec 4, 2020
Accession:
VCV000136753.13
Variation ID:
136753
Description:
single nucleotide variant
#
SCV Submitter Clinical significance Review status Collection method Number of
individuals
Number of
families
Interpreted condition
(Affected status)
Allele origin Clinical features
(Affected status)
Comments on
clinical features
Indication for testing Zygosity Citations Links Comments on
clinical significance
Comments on
evidence
Family history Segregation
observed
Age Sex Ethnicity/Population
group
Geographic origin Tissue Secondary finding Study name Method Result Testing laboratory Testing laboratory
interpretation
Date interpretation
reported to submitter
1 SCV000511714.1 Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics Likely Benign criteria provided,
single submitter
clinical testing not provided (not provided ) germline Converted during submission to Likely benign.
1 SCV000706592.2 Eurofins NTD, LLC Likely benign criteria provided,
single submitter
clinical testing 1 not specified (unknown ) germline 1 Single Heterozygote http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHRNA2 mixed
1 SCV001143532.1 Athena Diagnostics Inc Benign criteria provided,
single submitter
clinical testing not provided (unknown ) germline PubMed: 24950454
1 SCV001440254.1 Institute of Human Genetics, University of Leipzig Medical Center Likely benign criteria provided,
single submitter
clinical testing Epilepsy, nocturnal frontal lobe, type 4 (yes ) unknown
1 SCV000848373.2 Ambry Genetics Likely benign criteria provided,
single submitter
clinical testing 1 Seizures (unknown ) germline In silico models in agreement (benign);Subpopulation frequency in support of benign classification
1 SCV000167705.12 GeneDx Benign criteria provided,
single submitter
clinical testing not specified (yes ) germline This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
1 SCV000898604.1 Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Uncertain significance criteria provided,
single submitter
clinical testing Epilepsy, nocturnal frontal lobe, type 4 (unknown ) germline CHRNA2 NM_000742.3 exon 6 p.Asp478Glu (c.1434C>A): This variant has not been reported in the literature but is present in 0.5% (685/126322) of European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs56344740). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:136753). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies predict that this variant will impact the protein (Dash 2014 PMID:24950454). However, these studies may not accurately represent human biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
1 SCV000473182.3 Illumina Laboratory Services,Illumina Benign criteria provided,
single submitter
clinical testing Epilepsy, nocturnal frontal lobe, type 4 (unknown ) germline 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
1 SCV000285613.6 Invitae Benign criteria provided,
single submitter
clinical testing Autosomal dominant nocturnal frontal lobe epilepsy (unknown ) germline