rs147253810
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.6078C>T(p.Val2026=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,603,832 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00085 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0017 ( 19 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.620
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
?
Variant 16-2109089-G-A is Benign according to our data. Variant chr16-2109089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109089-G-A is described in Lovd as [Benign]. Variant chr16-2109089-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.62 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000847 (129/152370) while in subpopulation SAS AF= 0.0118 (57/4832). AF 95% confidence interval is 0.00935. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High AC in GnomAd at 129 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.6078C>T | p.Val2026= | synonymous_variant | 15/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.6078C>T | p.Val2026= | synonymous_variant | 15/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000847 AC: 129AN: 152252Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00191 AC: 466AN: 243746Hom.: 4 AF XY: 0.00256 AC XY: 341AN XY: 133448
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GnomAD4 exome AF: 0.00166 AC: 2415AN: 1451462Hom.: 19 Cov.: 34 AF XY: 0.00204 AC XY: 1471AN XY: 720444
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 19, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Polycystic kidney disease, adult type Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 19, 2018 | - - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Val2026Val variant was identified as a polymorphism in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs147253810) as “NA”, with a minor allele frequency of 0.0016 (8 of 5000 chromosomes) in the 1000 Genome Project; the NHLBI GO Exome Sequencing Project in 8 of 8572 European American chromosomes, the Exome Aggregation Consortium database (March 14, 2016) in 245 (3 homozygous) of 114048 chromosomes (freq. 0.002148) in the following populations: South Asian in 199 of 16220 chromosomes (freq. 0.01227), European (Non-Finnish) in 42 of 61954 chromosomes (freq. 0.0006779), Latino in 2 of 11342 chromosomes (freq. 0.0001763), African in 1 of 8888 chromosomes (freq. 0.0001125), and other in 1 of 840 chromosomes (freq. 0.00119), but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was identified in GeneInsight COGR (as benign) and the ADPKD Mutation Database (as likely neutral). The p.Val2026Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant is classified as benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | PKD1: BP4, BP7, BS1, BS2 - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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