ClinVar Genomic variation as it relates to human health

DDB2: BP4, BS2

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 is associated with the following publications: (PMID: 24728327)

The DDB2 p.Ala410Thr variant was not identified in the literature nor was it identified in LOVD 3.0 or Cosmic. The variant was identified in dbSNP (ID: rs143049891) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 690 of 276356 chromosomes (2 homozygous) at a frequency of 0.002497 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: European (non-Finnish) in 526 of 126090 chromosomes (freq: 0.004172), European (Finnish) in 52 of 24444 chromosomes (freq: 0.002127), Other in 14 of 7086 chromosomes (freq: 0.001976), Latino in 66 of 34698 chromosomes (freq: 0.001902), African in 27 of 24524 chromosomes (freq: 0.001101) and South Asian in 5 of 29572 chromosomes (freq: 0.000169), but was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Ala410 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely 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).