rs529066905

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The ENST00000262304.9(PKD1):​c.776G>A​(p.Cys259Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000261 in 1,533,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.18
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 Likely_benign. Variant got -1 ACMG points.

BS2
High AC in GnomAd4 at 37 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKD1NM_001009944.3 linkuse as main transcriptc.776G>A p.Cys259Tyr missense_variant 5/46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkuse as main transcriptc.776G>A p.Cys259Tyr missense_variant 5/461 NM_001009944.3 ENSP00000262304 P5P98161-1
PKD1ENST00000423118.5 linkuse as main transcriptc.776G>A p.Cys259Tyr missense_variant 5/461 ENSP00000399501 A2P98161-3

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000486
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000152
AC:
21
AN:
138576
Hom.:
0
AF XY:
0.000159
AC XY:
12
AN XY:
75438
show subpopulations
Gnomad AFR exome
AF:
0.000148
Gnomad AMR exome
AF:
0.0000814
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000313
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000264
AC:
364
AN:
1381378
Hom.:
0
Cov.:
32
AF XY:
0.000271
AC XY:
185
AN XY:
682724
show subpopulations
Gnomad4 AFR exome
AF:
0.000159
Gnomad4 AMR exome
AF:
0.0000837
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000503
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000317
Gnomad4 OTH exome
AF:
0.000191
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000486
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.000178
ExAC
AF:
0.0000618
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 21, 2022In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17582161, 33502802, Izzi2022[paper], 31738409) -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsAug 17, 2021- -
PKD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 21, 2023The PKD1 c.776G>A variant is predicted to result in the amino acid substitution p.Cys259Tyr. This variant was reported in an individual with polycystic kidney disease (Rossetti et al. 2007. PubMed ID: 17582161). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2168217-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Benign
0.93
DEOGEN2
Benign
0.27
T;.
Eigen
Uncertain
0.34
Eigen_PC
Benign
0.20
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.66
T;T
M_CAP
Pathogenic
0.84
D
MetaRNN
Uncertain
0.73
D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Uncertain
2.7
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.3
N;N
REVEL
Uncertain
0.40
Sift
Uncertain
0.010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.70
MVP
0.75
ClinPred
0.14
T
GERP RS
4.4
Varity_R
0.34
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs529066905; hg19: chr16-2168217; API