Submissions for variant NM_000297.4(PKD2):c.1359A>G (p.Pro453=)

gnomAD frequency: 0.00985  dbSNP: rs17013754

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078579	SCV000110435	benign	not specified	2015-12-14	criteria provided, single submitter	clinical testing
Invitae	RCV000233733	SCV000284557	benign	Autosomal dominant polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078579	SCV000303526	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001000326	SCV000451554	likely benign	Polycystic kidney disease 2	2018-01-12	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics Inc	RCV000712678	SCV000843197	benign	not provided	2017-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000326	SCV001157035	benign	Polycystic kidney disease 2	2019-08-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000712678	SCV001752283	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001000326	SCV002802521	likely benign	Polycystic kidney disease 2	2022-04-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291923	SCV000592879	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Pro453Pro variant was not identified in the literature nor was it identified in the PKD2-LOVD database. The variant was identified in dbSNP (ID: rs17013754) as “With Benign allele.” This variant was identified in the 1000 Genomes Project in 60 of 5000 chromosomes (frequency: 0.012); The HAPMAP-YRI in 6 of 114 chromosomes (frequency: 0.05263158); NHLBI GO Exome Sequencing Project in 2 of 8600 European American (frequency: 0.000232558), and 133 of 4406 African American alleles (frequency: 0.03018611); Exome Aggregation Consortium database (August 8, 2016) in 388 (6 homozygous) of 121396 chromosomes (frequency: 0.003196) in the following populations: African in 346 of 10406 chromosomes (frequency: 0.03325) Latino in 17 of 11572 chromosomes (frequency: 0.001469) South Asian in 13 of 16510 chromosomes (frequency: 0.0007874) European (Non-Finnish) in 9 of 66734 chromosomes (frequency: 0.0001349), and Other in 3 of 908 chromosomes (frequency0.003304) but was not seen in East Asian and European (Finnish) populations, increasing the likelihood this could be a low frequency benign variant; ClinVar and Clinvitae database (Benign by Emory Genetics, Invitae, and Prevention Genetics); GeneInsight COGR database (benign by LMM) and ADPKD Mutation Database (Likely neutral). The p.Pro453Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, and 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.