rs561467860
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting
The NM_001009944.3(PKD1):c.1557C>T(p.Thr519=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,531,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -10.4
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
?
Variant 16-2116882-G-A is Benign according to our data. Variant chr16-2116882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116882-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-10.4 with no splicing effect.
BS2
?
High AC in GnomAd4 at 25 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 | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.1557C>T | p.Thr519= | synonymous_variant | 7/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.1557C>T | p.Thr519= | synonymous_variant | 7/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000106 AC: 14AN: 132110Hom.: 0 AF XY: 0.000125 AC XY: 9AN XY: 71828
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GnomAD4 exome AF: 0.000109 AC: 151AN: 1379616Hom.: 0 Cov.: 30 AF XY: 0.000122 AC XY: 83AN XY: 682060
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | PKD1: BP4, BP7 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2021 | This variant is associated with the following publications: (PMID: 22383692) - |
Polycystic kidney disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Thr519= variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with autosomal dominant polycystic kidney disease (Rossetti 2012). It was also identified in dbSNP (ID: rs561467860) as "With Likely benign allele", ClinVar (classified as likely benign by Athena Diagnostics Inc.) and in the ADPKD Mutation Database (as likely neutral). The variant was not identified in the LOVD 3.0 or PKD1-LOVD databases. It was identified in control databases in 18 of 158020 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European in 16 of 62580 chromosomes (freq: 0.0003) and East Asian in 2 of 11602 chromosomes (freq: 0.0002), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. In addition, we cannot be certain that data from control databases are specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Thr519= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. This variant was identified with a co-occurring, pathogenic variant in PKD2 (c.1081C>T, p.Arg361*), increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 01, 2016 | - - |
Polycystic kidney disease, adult type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 23, 2021 | - - |
PKD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 26, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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