Table 3.

Pathogenic and probable pathogenic mutations with VAF≥30%, by cyst (n=103)

Patient	Cyst	Gene	Chr	HGVSc	HGVSp	Read Depth	VAF	CADD Score	Pathway (Reactome)	P Value	rs#/COSMIC (ExAC%)
BJA001578	A23	PKD1	chr16	c.1560_1561insTAACACCGAC	p.Leu521Ter	10	0.8		VxPx cargo-targeting to cilium	0.006
	B13	B3GNT3	chr19	c.156_157insCCCCCC	p.Pro52_Pro53insProPro	28	0.61		O-linked glycosylation of mucins	0.000
	B16	PKD1	chr16	c.6485G>A	p.Arg2162Gln	753	0.35	25.8	VxPx cargo-targeting to cilium	0.009
	B16	SMARCAD1	chr4	c.2572T>C	p.Phe858Leu	66	0.48	23	*	*
	B14	STK19	chr6	c.328G>T	p.Asp110Tyr	42	0.31	19.46	*	*
	A23	C4orf21	chr4	c.3919C>A	p.His1307Asn	15	0.4	28.3	*	*
	A24	PKD1	chr16	c.3929_3930del	p.Asp1310Glyfs*120 (LOH)	12	1.00		VxPx cargo-targeting to cilium	0.006
BS9001424	A3	PKD1	chr16	c.11888G>A	p.Trp3963Ter	18	0.56	41	VxPx cargo-targeting to cilium	0.039
	A3	PSME4	chr2	c.4821_4832delCCCAGTGGAAAA	p.Pro1608_Asn1611del	20	0.5		*	*
	A3	WARS2	chr1	c.404G>T	p.Arg135Leu	46	0.48	35	Mitochondrial tRNA aminoacylation	0.039	rs147962776 (0.03)
	A3	PAPD7	chr5	c.1371_1373delGTC	p.Met457_Ser458delinsIle	204	0.48		*	*
	A3	ITGA7	chr12	c.386G>A	p.Arg129Gln	91	0.46	19.41	Laminin interactions	0.06	rs376167554 (0.002)
	A3	NCOR1	chr17	c.5506G>A	p.Val1836Met	66	0.39	24.9	NR1D1 (REV-ERBA) represses gene expression	0.006
	A3	USP51	chrX	c.663_666delTGGG	p.Ser221ArgfsTer22	32	0.59		*	*
	A3	INSIG2	chr2	c.83T>G	p.Leu28Trp	61	0.57	26.5	*	*
	A3	NAA15	chr4	c.175delA	p.Ile59SerfsTer34	48	0.56		*	*	rs375319596 (NA)
	A3	C1orf74	chr1	c.23C>A	p.Ser8Ter	101	0.53	36	*	*
	A3	BCOR	chrX	c.4690A>G	p.Arg1564Gly	76	0.51	31	*	*
	A3	EMX2	chr10	c.651A>T	p.Glu217Asp	56	0.48	19.56	*	*
	A3	ELP3	chr8	c.1486–1G>T		77	0.48	21.1	*	*
	A3	SIDT1	chr3	c.2269G>A	p.Ala757Thr	17	0.47	34	*	*	COSM201721
	A3	RAB23	chr6	c.398A>T	p.Asn133Ile	110	0.46	22.8	*	*
	A3	ZBTB40	chr1	c.435_436delAG	p.Gln145HisfsTer7	47	0.45		*	*
	A3	DMXL1	chr5	c.4099C>A	p.His1367Asn	52	0.44	15.66	*	*
	A3	CRYZ	chr1	c.411_414delTCGA	p.Tyr137Ter	143	0.4		*	*
	A3	QRICH2	chr17	c.4226C>T	p.Ala1409Val	43	0.33	21.4	*	*
	A2	NOX5	chr15	c.844A>C	p.Ser282Arg	25	0.32	23.9	*	*	rs150003957 (1.67) COSM964378
CDS001574	A21	PKD1	chr16	c.11817G>A	p.Trp3939Ter	27	0.56	39	VxPx cargo-targeting to cilium	0.006
	B7	AKT2	chr19	c.1016T>G	p.Val339Gly	13	0.31	27.1	PKB-mediated events	0.001
	B12	PKD1	chr16	c.10084del	p.Gln3362Serfs*35 (LOH)	304	0.96		VxPx cargo-targeting to cilium	0.006
	B12	SNX8	chr7	c.910C>T	p.Gln304Ter	66	0.44	36	*
	A20	SPTY2D1	chr11	c.2044C>G	p.Leu682Val	46	0.3	20.8	*	*
	B7	WDFY3	chr4	c.2039A>C	p.Gln680Pro	13	0.38	16.39	*	*
	B7	SON	chr21	c.331C>A	p.His111Asn	32	0.38	23.3	*	*
	B8	PRR12	chr19	c.5284G>A	p.Gly1762Arg	86	0.37	19.09	*	*
	B9	LRCH1	chr13	c.705G>T	p.Leu235Phe	65	0.31	28.5	*	*
	B10	TINAGL1	chr1	c.961C>T	p.Arg321Cys	64	0.38		*	*
CMJ001593	A30	PARP14	chr3	c.2768C>A	p.Ser923Tyr	79	0.32	26	Nicotinamide salvaging	0.006
	A30	ZG16	chr16	c.157C>T	p.Arg53Trp	64	0.31	30	*	*
	A30	ANKK1	chr11	c.754C>T	p.Gln252Ter	52	0.31	26.8	*	*
	A31	CCT4	chr2	c.814A>T	p.Met272Leu	27	0.56	25.9	Folding of actin by CCT/TriC	0.003
	A31	PNISR	chr6	c.1651T>C	p.Ser551Pro	12	0.67	22.9	*	*
	A31	EVI5	chr1	c.1327A>T	p.Ile443Phe	41	0.44	25.1	*	*
	A33	MVP	chr16	c.1807G>A	p.Val603Ile	51	0.45	26	*	*
	A33	CWF19L2	chr11	c.1880G>T	p.Gly627Val	84	0.4	23	*	*
	A34	SMARCAD1	chr4	c.2572T>C	p.Phe858Leu	22	0.41	23	*	*
DR9001565	A15	PKD1a	Chr16	c.9504C>G	p.Phe3168Leu (LOH)	66	0.88		VxPx cargo-targeting to cilium	0.006
	A15	C1QL2	chr2	c.590G>T	p.Cys197Phe	10	0.3	31	*	*
	A16	THRAP3	chr1	c.2701C>T	p.Arg901Ter	9	0.33	41	Transcriptional regulation of white adipocyte differentiation	0.008
	A17	DOCK4	chr7	c.4286_4287delAA	p.Lys1429ArgfsTer3	124	0.39		Megakaryocyte development and platelet production	0.03
	A17	CASC5	chr15	c.4886C>T	p.Thr1629Ile	29	0.38	17.62	Nucleosome assembly	0.01
	A18	PCDHGB6	chr5	c.1415C>A	p.Ala472Glu	14	0.3	20.8	*	*
	B3	ACSS1	chr20	c.500G>A	p.Arg167His	12	0.42	31	Ethanol oxidation	0.001
	B4	PKD1	chr16	c.6282G>T	p.Trp2094Cys	9	0.33	26.8	VxPx cargo-targeting to cilium	0.006
	B4	KIF17	chr1	c.3002G>C	p.Arg1001Pro	15	0.33	34	Intraflagellar transport		COSM182818
	B5	PADI4	chr1	c.979G>C	p.Ala327Pro	69	0.3	23.8	Chromatin modifying enzymes	0.04	rs145819522 (0.15)
	B5	WRNIP1	chr6	c.1120G>A	p.Val374Met	80	0.33	32	*	*
	B6	UBE3C	chr7	c.1332G>T	p.Arg444Ser	16	0.31	23.2	Antigen processing: ubiquitination and proteasome degradation	0.03
JS9001595	B26	LILRB5	chr19	c.1652A>C	p.Gln551Pro	17	0.35	16.26	Immunoregulatory interactions: lymphoid and a nonlymphoid cell	0.03
	B27	PNPLA6	chr19	c.2966+2T>G		17	0.35		Glycerophospholipid catabolism	0.002
	B27	ZNF518B	chr4	c.641A>C	p.Glu214Ala	45	0.96	27.7	*	*
	B27	MYOM3	chr1	c.3751A>C	p.Lys1251Gln	20	0.3	23.2	*	*
	B29	PCSK5	chr9	c.1312G>T	p.Val438Leu	13	0.31	26.8	NGF processing	0.001
	B31	PKD1	chr16	c.10220+2T>G		39	0.46		VxPx cargo-targeting to cilium	0.008
	B31	KCNC3	chr19	c.*81A>C		16	0.44		Voltage-gated potassium channels	0.02
	B32	CRCP	chr7	c.145–1G>T		19	0.32		RNA polymerase III chain elongation	0.003
	B33	PKD1	chr16	c.3184C>T	p.Gln1062Ter	27	0.63	35	VxPx cargo-targeting to cilium	0.006
	B33	ANGPTL3	chr1	c.124G>C	p.Asp42His	73	0.4	28.4	Assembly of active LPL and LIPC lipase complexes	0.005	rs199772471 (0.02)
BH9002280	B34	PKD2	chr4	c.2409delA	p.Ser804ValfsTer40	80	0.3		VxPx cargo-targeting to cilium	0.004
	B35	CEP97	chr3	c.1142A>T	p.Asp381Val	33	0.3	23.2	Anchoring of the basal body to the plasma membrane	0.009
	L2	PKD2	chr4	c.242C>A	p.Ser81Ter	14	0.57	36	VxPx cargo-targeting to cilium	0.004
	L5	PRKCI	chr3	c.280G>C	p.Glu94Gln	35	0.34	24.3	p75NTR recruits signaling complexes	0.003
	L5	SCAF1	chr19	c.619_620insCCCCCCCCC	p.Ser207_Pro208insProProPro	12	0.33		*	*
	R2	PKD2	chr4	c.1392A>G	p.=	32	0.34		VxPx cargo-targeting to cilium	0.004
	R7	PKD2	chr4	c.1366C>T	p.Gln456Ter	98	0.38	42	VxPx cargo-targeting to cilium	0.004
	B36	NXNL1	chr19	c.577C>G	p.Arg193Gly	9	0.44	23.2	*	*
	R8	YBX3	chr12	c.40_42delACC	p.Thr14del	16	0.31		*	*
	L5	SCAF1	chr19	c.619_620insCCCCCCCCC	p.Ser207_Pro208insProProPro	12	0.33		*	*
PJ9001456	A10	PKD1a	chr16	c.7655_7658 delinsTTG	p.Ala2552Valfs*68	779	0.32		VxPx cargo-targeting to cilium	0.006
	A11	MIB2	chr1	c.2092G>A	p.Glu698Lys	10	0.3	22.8	Signaling by NOTCH1 HD Domain Mutants in Cancer	0.003
	A7	PKD1a	chr16	c.6364delG	p.Val2122Lysfs*3 (LOH)	804	0.92		VxPx cargo-targeting to cilium	0.008
	A7	SVIL	chr10	c.4121T>G	p.Leu1374Arg	10	0.3	25.8	*	*
	A8	PKD1a	chr16	c.348_352del	p.Asn116Lysfs*2	793	0.3		VxPx cargo-targeting to cilium	0.006
	A9	PKD1	chr16	c.8016+1delG		12	0.5		VxPx cargo-targeting to cilium	0.006
	B1	SLC14A2	chr18	c.2548A>C	p.Asn850His	19	0.32	22.2	Transport -bile salts, organic acids, metal ions, amine compounds	0.03
	B1	URGCP	chr7	c.173A>C	p.Asn58Thr	14	0.36	26.9	*	*
	B1	DNAH5	chr5	c.5335G>T	p.Val1779Phe	28	0.32	27.9	*	*
	B2	EIF3A	chr10	c.330G>T	p.Gln110His	33	0.36	23.5	Formation of the ternary complex, subsequently 43S complex	0.01
	B2	RGS1	chr1	c.553G>T	p.Asp185Tyr	59	0.32	33	Gα(i) signaling events	0.004
RP9001591	B18	PKD1	chr16	c.8996_8997insG	p.Phe2999LeufsTer70	64	0.33		VxPx cargo-targeting to cilium	0.006
	B18	ATP2B3	chrX	c.2866G>A	p.Gly956Arg	92	0.3	27	Reduction of cytosolic Ca++ levels	0.003
	B20	CACNA2D1	chr7	c.668G>T	p.Trp223Leu	12	0.42	35	Phase 2 – plateau phase	0.00	COSM747982
	B20	PRRC2B	chr9	c.1997A>C	p.Gln666Pro	11	0.36	25.6	*	*
	B21	PKD1a	chr16	c.G10549T	p.Glu3517* (LOH)	140	0.97		VxPx cargo-targeting to cilium	0.006
	B21	KIF26A	chr14	c.5624C>T	p.Pro1875Leu	75	0.39	22	Kinesins	0.01	rs200461988 (0.05)
	B21	KISS1R	chr19	c.828_832delGGGCC	p.Trp276CysfsTer28	72	0.35		Peptide ligand-binding receptors	0.03
	B22	SMARCA2	chr9	c.667_675delCAGCAGCAG	p.Gln226_Gln228del	111	0.36		RUNX1 interacts with cofactors whose precise effect on RUNX1 not known	0.003
	B23	STON2	chr14	c.1498C>T	p.Arg500Trp	22	0.36	29.3	Cargo recognition for clathrin-mediated endocytosis	0.0267	rs149119701 (0.002)
	B23	ATAD2B	chr2	c.458_465delATGGGGAC	p.Asp153AlafsTer7	29	0.52		*	*
	B23	SELE	chr1	c.922C>T	p.Arg308Cys	76	0.41	23	*	*
	B24	KIF17	chr1	c.3002G>C	p.Arg1001Pro	16	0.38	34	Intraflagellar transport	0.01	COSM182818
	B24	ABCA13	chr7	c.86A>C	p.Glu29Ala	11	0.36	31	*	*
	B24	PRRC2B	chr9	c.1997A>C	p.Gln666Pro	16	0.31	25.6	*	*

The pathogenic potential of missense variants was evaluated using the computational analysis tool CADD, which enables scoring of deleteriousness of SNVs and indels. A CADD value of ≥15 suggests the variant is likely pathogenic (http://cadd.gs.washington.edu/). Significantly mutated WES variants were further filtered using a 30% VAF cutoff and a population allele frequency of 5% (http://exac.broadinstitute.org/). Variants were further subjected for pathway analysis to identify overrepresented pathways using Reactome (https://reactome.org/) and verified with David (https://david.ncifcrf.gov/). Only significantly overrepresented pathways with low P values (<0.05), i.e., the probability that overlap between the queried variant and pathway occurs by chance, were reported. Cysts/variants for which no pathways were identified are indicated by *. Chr, chromosome; HGVSc, the Human Genome Variation Society coding sequence name; HGVSp, the Human Genome Variation Society protein sequence name; rs#/COSMIC, Catalogue Of Somatic Mutations In Cancer; ExAC, The Exome Aggregation Consortium; tRNA, transfer ribonucleic acid.

^aPKD1 genotyping performed by long-range PCR next-generation sequencing.