16-2116856-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

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 (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

5
9
5

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain C-type lectin (size 116) in uniprot entity PKD1_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_001009944.3
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 id is 433946.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2116856-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKD1NM_001009944.3 linkc.1583A>G p.Tyr528Cys missense_variant 7/46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkc.1583A>G p.Tyr528Cys missense_variant 7/461 NM_001009944.3 ENSP00000262304.4 P98161-1

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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.31e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal dominant polycystic kidney disease Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 21, 2022The 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 v4.3

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;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Benign
-0.93
T
MutationAssessor
Uncertain
2.6
M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.96
MutPred
0.92
Gain of disorder (P = 0.0202);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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750798165; hg19: chr16-2166857; API