ClinVar

Description

The PKD1 p.Glu2548Gln variant was identified in 3 of 604 proband chromosomes (frequency: 0.005) from individuals or families with AKPKD, and was not identified in 200 control chromosomes from healthy individuals (Bataille_2011, Rossetti_2012, Watnick_1999). The variant was also identified in dbSNP (ID: rs rs28369051) with no allele association indicated and listed in 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383), in NHLBI GO Exome Sequencing Project (ESP) in 2 of 8130 European American (frequency: 0.0002) and 303 in 4042 African American alleles (frequency: 0.075). The variant is also identified in The Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) in 541 of 500090 chromosomes (frequency: 0.011) of which 30 homozygotes are of African ethnicity increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Furthermore, the variant is listed in GeneInsight COGR database by LMM 1x as benign, in MutDB 1x as a polymorphism, and in ARPKD database 6x as likely neutral. The p. Glu2548residue 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. Furthermore, the variant amino acid (Gln) is present in dog, increasing the likelihood that this variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.