rs867790304
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001009944.3(PKD1):c.-195G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 216,268 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 (no stars).
Frequency
Genomes: 𝑓 0.00096 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 5_prime_UTR
NM_001009944.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.276
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 -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
?
Variant 16-2135884-C-T is Benign according to our data. Variant chr16-2135884-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433936.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
?
High AC in GnomAd4 at 143 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.-195G>A | 5_prime_UTR_variant | 1/46 | ENST00000262304.9 | ||
PKD1 | NM_000296.4 | c.-195G>A | 5_prime_UTR_variant | 1/46 | |||
PKD1 | XM_047434208.1 | c.-195G>A | 5_prime_UTR_variant | 1/48 | |||
PKD1 | XM_047434209.1 | c.-195G>A | 5_prime_UTR_variant | 1/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.-195G>A | 5_prime_UTR_variant | 1/46 | 1 | NM_001009944.3 | P5 | ||
PKD1 | ENST00000423118.5 | c.-195G>A | 5_prime_UTR_variant | 1/46 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000957 AC: 143AN: 149394Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.000315 AC: 21AN: 66762Hom.: 0 Cov.: 0 AF XY: 0.000442 AC XY: 14AN XY: 31694
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GnomAD4 genome ? AF: 0.000956 AC: 143AN: 149506Hom.: 0 Cov.: 31 AF XY: 0.000986 AC XY: 72AN XY: 73014
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1, Promoter region, c.-195G>A variant was not identified in the literature nor was it identified in dbSNP, NHLBI GO Exome Sequencing Project, Exome Aggregation Consortium database (March 14, 2016) Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database PKD1-LOVD and PKD1-LOVD 3.0 databases. To identify conserved putative transcription factor-binding sites, a study cloned and characterized the 5'-flanking regions of the murine and canine Pkd1 genes and performed a multispecies comparison by including sequences from the human and Fugu rubripes orthologues as well as the Pkd2 promoters from mouse and human. Sequence analysis revealed a variety of conserved putative binding sites for transcription factors and no TATA-box element. Nine elements were conserved in the mammalian Pkd1 promoters: AP2, E2F, E-Box, EGRF, ETS, MINI, MZF1, SP1, and ZBP-89. Interestingly, six of these elements were also found in the mammalian Pkd2 promoters. Deletion studies with the mouse Pkd1 promoter showed that a approximately 280 bp fragment is capable of driving luciferase reporter gene expression, whereas reporter constructs containing larger fragments of the Pkd1 promoter showed a lower activity. Furthermore, mutating a potential E2F-binding site within this 280 bp fragment diminished the reporter construct activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the Pkd1 gene. The data define a functional promoter region for Pkd1 and imply that E2F, EGRF, Ets, MZF1, Sp1, and ZBP-89 are potential key regulators of PKD1 and PKD2 in mammals (Lantinga-van Leeuwen 2005). 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 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