Submissions for variant NM_000297.4(PKD2):c.290AGG[7] (p.Glu102dup)

dbSNP: rs750077647

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173103	SCV000224188	likely benign	not specified	2014-07-15	criteria provided, single submitter	clinical testing
Invitae	RCV000200241	SCV000255284	benign	Autosomal dominant polycystic kidney disease	2024-01-26	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000173103	SCV000614572	benign	not specified	2017-04-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000987456	SCV001136751	benign	Polycystic kidney disease 2	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001356905	SCV001755699	benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20950398, 17574468, 22863349, 21719175, 22508176)
Genetic Services Laboratory, University of Chicago	RCV000173103	SCV002064908	benign	not specified	2017-11-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000987456	SCV002797362	likely benign	Polycystic kidney disease 2	2022-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001356905	SCV004011545	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PKD2: BS1
PreventionGenetics, part of Exact Sciences	RCV003917593	SCV004734162	benign	PKD2-related condition	2019-10-30	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356905	SCV001552191	likely benign	not provided		no assertion criteria provided	clinical testing	The PKD2 p.Glu102dup variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from French, British, and North America individuals or families with ADPKD (Audrezet 2012, Garcia-Gonzalez 2007). There is conflicting evidence in the literature and databases. The variant was identified in a 54 year old male patient with bilateral multicystic kidneys and situs inverus, the duplication segregating with the disease (cystic kidneys) in 1 of the proband’s children and was absent in the 3 unaffected children suggesting that the variant is disease causing (Bataille 2011). The variant was identified in dbSNP (ID: rs547253972) as “NA”, Clinvitae database (classification likely benign and benign), the ClinVar database (classification benign by Invitae and likely benign by Emory Genetics), the ADPKD Mutation Database (classification indeterminate), and COSMIC (1X in a lung carcinoma). This variant was also identified in the 1000 Genomes Project in 37 of 5000 chromosomes (frequency: 0.0074), HAPMAP-AFR in 32 of 1322 chromosomes (frequency: 0.0242), HAPMAP-AMR in 3 of 694 chromosomes (frequency: 0.0043), HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), and in the Exome Aggregation Consortium database (August 8th 2016) in 928 of 11372 chromosomes (freq. 0.0816) in the following populations: South Asian in 662 of 7216 chromosomes (freq. 0.09), European (Non-Finnish) in 229 of 3242 chromosomes (freq. 0.07), Other in 8 of 128 chromosomes (freq. 0.06), Latino in 8 of 164 chromosomes (freq. 0.05), African in 16 of 442 chromosomes (freq. 0.04), East Asian in 5 of 172 chromosomes (freq. 0.02) but was not seen in the Finnish populations. This high frequency of observations in a control database strongly suggests that the variant is not clinically significant. 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. This variant is an in-frame duplication resulting in the addition of a Glutamic acid residue at codon 102; the impact of this alteration on PKD2 protein function is not known. 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.