rs529066905
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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
ENST00000262304.9 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 6.18
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]
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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 |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.776G>A | p.Cys259Tyr | missense_variant | 5/46 | 1 | NM_001009944.3 | ENSP00000262304 | P5 | |
PKD1 | ENST00000423118.5 | c.776G>A | p.Cys259Tyr | missense_variant | 5/46 | 1 | ENSP00000399501 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152074Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000152 AC: 21AN: 138576Hom.: 0 AF XY: 0.000159 AC XY: 12AN XY: 75438
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GnomAD4 exome AF: 0.000264 AC: 364AN: 1381378Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 185AN XY: 682724
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GnomAD4 genome AF: 0.000243 AC: 37AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74392
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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 submitter | clinical testing | GeneDx | Feb 21, 2022 | In 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 submitter | clinical testing | Athena Diagnostics | Aug 17, 2021 | - - |
PKD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2023 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at