rs62038811
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.12765C>T(p.Pro4255=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,609,788 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0043 ( 1 hom., cov: 34)
Exomes 𝑓: 0.0069 ( 48 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.62
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=-0.85).
BP6
?
Variant 16-2089874-G-A is Benign according to our data. Variant chr16-2089874-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2089874-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.62 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00426 (649/152354) while in subpopulation NFE AF= 0.00783 (533/68032). AF 95% confidence interval is 0.00728. There are 1 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 649 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.12765C>T | p.Pro4255= | synonymous_variant | 46/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.12765C>T | p.Pro4255= | synonymous_variant | 46/46 | 1 | NM_001009944.3 | P5 | |
PKD1 | ENST00000423118.5 | c.12762C>T | p.Pro4254= | synonymous_variant | 46/46 | 1 | A2 | ||
PKD1 | ENST00000472577.1 | n.793C>T | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00427 AC: 650AN: 152240Hom.: 1 Cov.: 34
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GnomAD3 exomes AF: 0.00379 AC: 891AN: 235318Hom.: 2 AF XY: 0.00402 AC XY: 518AN XY: 128950
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GnomAD4 exome AF: 0.00687 AC: 10013AN: 1457434Hom.: 48 Cov.: 31 AF XY: 0.00681 AC XY: 4938AN XY: 724876
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GnomAD4 genome ? AF: 0.00426 AC: 649AN: 152354Hom.: 1 Cov.: 34 AF XY: 0.00360 AC XY: 268AN XY: 74498
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2020 | This variant is associated with the following publications: (PMID: 10200984, 11058904, 22008521, 22383692) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PKD1: BP4, BP7, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Polycystic kidney disease, adult type Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 11, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 11, 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.Pro4255= variant was identified in 16 of 1176 proband chromosomes (frequency: 0.014) from Spanish, Slovenian, Italian, American and French individuals or families with ADPKD, and considered to be a polymorphism based on being a silent change or through family studies (Aguiari 2000, Badenas 1999, Vouk 2006, Tan 2009, Bataille 2011, Rossetti 2001, Rossetti 2012). The variant was also identified in dbSNP (ID: rs62038811) “NA”, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014), HAP-MAP populations: HAPMAP-EUR in 5 of 1006 chromosomes (frequency: 0.005), HAPMAP-AFR in 1 of 1322 chromosomes (frequency: 0.0008), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), in the NHLBI GO Exome Sequencing Project in 48 of 8542 European American (frequency: 0.0056) and in 12 of 4334 (frequency: 0.0028) African American alleles; and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 374 (1 homozygous) of 48494 chromosomes (frequency: 0.0077) from a population of European (Non-Finnish), in 5 of 3334 chromosomes (frequency: 0.0015) from Europe (Finnish), in 9 of 6810 chromosomes from African, in 9 of 7788 chromosomes (frequency: 0.0012) from Latin regions and in 6 of 13494 chromosomes (frequency: 0.0004) from South Asia, increasing the likelihood this could be a low frequency benign variant. The variant was not identified in East Asian or other populations in the ExAC database. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (p.Trp1243X) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Pro4255= variant does not have clinical significance. The p.Pro4255= 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 meets our laboratory criteria to be classified as benign. - |
Computational scores
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Name
Calibrated prediction
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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