rs754894798
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBP6_ModerateBP7BS2_Supporting
The NM_001009944.3(PKD1):c.8136C>T(p.Ile2712Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,557,892 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 0.00011 ( 0 hom., cov: 20)
Exomes 𝑓: 0.00022 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.589
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 -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 16-2104523-G-A is Benign according to our data. Variant chr16-2104523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448013.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2104523-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.589 with no splicing effect.
BS2
High AC in GnomAd4 at 17 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKD1 | NM_001009944.3 | c.8136C>T | p.Ile2712Ile | synonymous_variant | 22/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000113 AC: 17AN: 149974Hom.: 0 Cov.: 20
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GnomAD3 exomes AF: 0.000237 AC: 36AN: 151988Hom.: 0 AF XY: 0.000207 AC XY: 17AN XY: 81962
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GnomAD4 exome AF: 0.000219 AC: 308AN: 1407800Hom.: 0 Cov.: 30 AF XY: 0.000206 AC XY: 144AN XY: 697830
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GnomAD4 genome 0.000113 AC: 17AN: 150092Hom.: 0 Cov.: 20 AF XY: 0.000109 AC XY: 8AN XY: 73286
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2016 | - - |
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.Ile2712= variant was not identified in the literature, nor was it identified in GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs754894798) as “N/A”, ADPKD Mutation Database (classified as likely neutral), the genome Aggregation Database (beta, October 19th 2016) in 37 of 176006 chromosomes (freq. 0.0002), the Exome Aggregation Consortium database (August 8th 2016) in 4 of 17182 chromosomes (freq. 0.0002) in the following populations: European in 3 of 6330 chromosomes (freq. 0.0005), Latino in 1 of 516 chromosomes (freq. 0.002), but was not seen in African, Asian, Finnish and Other populations. The p.Ile2712= 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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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at