ClinVar Genomic variation as it relates to human health

Converted during submission to Likely benign.

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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.

This variant is associated with the following publications: (PMID: 30467950)

Variant summary: CHRNG c.125G>A (p.Arg42Gln) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 282714 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHRNG causing Lethal Multiple Pterygium Syndrome - CHRNG Related phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

CHRNG: BS2

The CHRNG p.Arg42Gln variant was not identified in the literature but was identified in dbSNP (ID: rs148468628) and ClinVar (classified as likely benign by Invitae and Center for Pediatric Genomic Medicine, Children's Mercy Hospital, and as uncertain significance by CeGat Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 661 of 282714 chromosomes (3 homozygous) at a frequency of 0.002338 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 52 of 10364 chromosomes (freq: 0.005017), European (non-Finnish) in 493 of 129072 chromosomes (freq: 0.00382), Other in 18 of 7222 chromosomes (freq: 0.002492), Latino in 67 of 35412 chromosomes (freq: 0.001892), European (Finnish) in 18 of 25114 chromosomes (freq: 0.000717), African in 11 of 24962 chromosomes (freq: 0.000441), East Asian in 1 of 19952 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The p.Arg42 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).