rs145850037
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.8298C>T(p.Ser2766Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,609,970 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2766S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0023 ( 9 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.730
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 -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 16-2103759-G-A is Benign according to our data. Variant chr16-2103759-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103759-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.73 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00134 (203/151802) while in subpopulation NFE AF= 0.00237 (161/67916). AF 95% confidence interval is 0.00207. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 203 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKD1 | NM_001009944.3 | c.8298C>T | p.Ser2766Ser | synonymous_variant | 23/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.00134 AC: 203AN: 151684Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00100 AC: 248AN: 247238Hom.: 0 AF XY: 0.000957 AC XY: 129AN XY: 134852
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GnomAD4 exome AF: 0.00233 AC: 3397AN: 1458168Hom.: 9 Cov.: 34 AF XY: 0.00216 AC XY: 1566AN XY: 725384
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GnomAD4 genome 0.00134 AC: 203AN: 151802Hom.: 0 Cov.: 31 AF XY: 0.00120 AC XY: 89AN XY: 74180
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | PKD1: BS1, BS2 - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2021 | This variant is associated with the following publications: (PMID: 12007219, 16430766, 17574468) - |
not specified Benign:1
| 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 | Mar 24, 2019 | - - |
Bile duct cancer Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Ser2766Ser variant was identified in 3 of 246 proband chromosomes (frequency: 0.012) from Japanese, Slovenian and American individuals or families with ADPKD, co-occurring with a pathogenic splicing PKD1 variant (c.8228-2delAG) in 1 Japanese individual (Garcia-Gonzalez 2007, Vouk 2006, Inoue 2002). The variant was also identified by our laboratory in an individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.2215C>T), increasing the likelihood that the p.Ser2766Ser variant does not have clinical significance. The variant was also identified in dbSNP (ID: rs145850037) as “NA”, and the ADPKD Mutation Database (classification likely neutral) and in the ClinVar database classified as Likely Benign by Prevention Genetics, but was not found in PKD1-LOVD, Clinvitae, GeneInsight COGR, MutDB and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project in 21 of 8552 European American alleles (frequency: 0.0025) and in 5 of 4352 African American alleles (frequency: 0.0011), the Exome Aggregation Consortium database (August 8, 2016) in 118 of 115912 chromosomes (freq. 0.0010)) in the following populations: European (Non-Finnish) in 95 of 63278 chromosomes (freq. 0.0015), African in 11 of 8940 chromosomes (freq. 0.0012), Latino in 9 of 11392 chromosomes (freq. 0.00079), South Asian in 3 of 16460 chromosomes (freq. 00018), but was not seen in East Asian, Finnish, or Other populations; increasing the likelihood this could be a low frequency benign variant. The p.Ser2766Ser 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's criteria to be classified as benign. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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