rs143017410
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.5373C>T(p.Asn1791=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,609,974 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0033 ( 5 hom., cov: 33)
Exomes 𝑓: 0.00037 ( 7 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.507
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=-0.89).
BP6
?
Variant 16-2109794-G-A is Benign according to our data. Variant chr16-2109794-G-A is described in ClinVar as [Benign]. Clinvar id is 256977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109794-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.507 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (501/152342) while in subpopulation AFR AF= 0.0111 (462/41568). AF 95% confidence interval is 0.0103. There are 5 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 500 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.5373C>T | p.Asn1791= | synonymous_variant | 15/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.5373C>T | p.Asn1791= | synonymous_variant | 15/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.00328 AC: 500AN: 152224Hom.: 5 Cov.: 33
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GnomAD3 exomes AF: 0.000710 AC: 172AN: 242232Hom.: 1 AF XY: 0.000483 AC XY: 64AN XY: 132380
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GnomAD4 exome AF: 0.000371 AC: 541AN: 1457632Hom.: 7 Cov.: 34 AF XY: 0.000331 AC XY: 240AN XY: 725102
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ClinVar
Significance: 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 | GeneDx | Jun 29, 2020 | This variant is associated with the following publications: (PMID: 22383692) - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 10, 2019 | - - |
not specified Benign:1
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 | Oct 01, 2018 | - - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Asn1791= variant was identified in 2 of 550 proband chromosomes (frequency: 0.003636) from individuals or families with autosomal dominant polycystic kidney disease (ADPKD) (Rossetti 2002, Rossetti 2012). The variant was also identified in dbSNP (ID: rs143017410) “With Benign allele,” ClinVar (as benign by Prevention Genetics), and ADPKD Mutation Database (2x as likely neutral). The variant was not identified in GeneInsight-COGR, LOVD 3.0, and PKD1-LOVD databases. The variant was identified in control databases in 265 of 269328 chromosomes at a frequency of 0.001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 234 of 22952 chromosomes (frequency: 0.0102), Ashkenazi Jewish in 6 of 9984 chromosomes (frequency: 0.00006), Latino in 20 of 34170 chromosomes (frequency: 0.00006), Other in 2 of 6290 chromosomes (frequency: 0.00003), and European Non-Finnish in 3 of 122142 chromosomes (frequency: 0.00002). 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 p.Asn1791= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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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