chr16-2116856-T-C

Variant names:

• chr16-2116856-T-C
• rs750798165
• NM_001009944.3:c.1583A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001009944.3(PKD1):​c.1583A>G​(p.Tyr528Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y528D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.13
• Publications: 8 publications found

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 16-2116856-T-C is Pathogenic according to our data. Variant chr16-2116856-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 433946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.1583A>G	p.Tyr528Cys	missense	Exon 7 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.1583A>G	p.Tyr528Cys	missense	Exon 7 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.1583A>G	p.Tyr528Cys	missense	Exon 7 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.1583A>G	p.Tyr528Cys	missense	Exon 7 of 46	ENSP00000399501.1
	PKD1	ENST00000568591.5	TSL:2	n.514A>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000457162.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377574 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 680826

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 36116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25120

East Asian (EAS) AF: 0.00 AC: 0 AN: 35924

South Asian (SAS) AF: 0.00 AC: 0 AN: 79430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4046

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074010

Other (OTH) AF: 0.00 AC: 0 AN: 57542

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease Pathogenic:1

Apr 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.1583A>G (p.Tyr528Cys) results in a non-conservative amino acid change located in the Polycystin cation channel domain (IPR006228) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1583A>G has been reported in the literature in multiple individuals affected with Autosomal Dominant Polycystic Kidney Disease (Garcia-Gonzalez_2007, Pei_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pei_2012). The most pronounced variant effect results in formation of cysts and increased apoptosis in cells expressing this mutant protein. The following publications have been ascertained in the context of this evaluation (PMID: 17574468, 22031115). ClinVar contains an entry for this variant (Variation ID: 433946). Based on the evidence outlined above, the variant was classified as pathogenic.

Autosomal dominant polycystic kidney disease Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Tyr528Cys variant was identified in 2 of 1066 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Garcia-Gonzalez 2007, Irazabal 2011). The variant was also identified in ADPKD Mutation Database (as highly likely pathogenic). The variant was not identified in dbSNP, Clinvitae, GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, NHLBI GO Exome Sequencing Project and Exome Aggregation Consortium database (March 14, 2016). The p.Tyr528 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, an in vivo study by Pei (2012), demonstrated that the p.Tyr528Cys variant affects an amino acid residue in the C-type lectin domain of polycystin-1 (PC1) that is highly-conserved across multiple species and moderately conserved across non-PC1 proteins with the same domain. The data from the study strongly suggest that this variant is a pathogenic PKD1 variant and that it functions as a hypomorphic allele in-vivo. The cell lines expressing the p.Tyr528Cys variant formed cysts in culture and demonstrated increased rates of growth and apoptosis. However, subjects affected with p.Tyr528Cys (PKD1) and a truncating PKD2 variant (p.Leu736X) had more severe renal disease than subjects affected with a pathogenic PKD1 or PKD2 variant alone. The individuals with p.Tyr528Cys clearly had better preserved renal function and have uniformly mild renal disease. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

PKD1-related disorder Pathogenic:1

Oct 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.1583A>G variant is predicted to result in the amino acid substitution p.Tyr528Cys. This variant has been reported in multiple unrelated individuals with polycystic kidney disease (Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Irazabal et al. 2011. PubMed ID: 21551026; Pei et al. 2012. PubMed ID: 22031115). At PreventionGenetics, we also found this variant previously in the heterozygous state in a patient tested for polycystic kidney disease. In vitro functional characterization suggests that this variant is deleterious (Pei et al. 2012. PubMed ID: 22031115). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Benign	0.61
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.92		Gain of disorder (P = 0.0202)
MVP		0.94
ClinPred		0.98	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750798165; hg19: chr16-2166857;