rs375408086
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_001009944.3(PKD1):c.8118C>T(p.Thr2706=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,580,882 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 0.00037 ( 0 hom., cov: 20)
Exomes 𝑓: 0.00058 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.33
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
?
Variant 16-2104541-G-A is Benign according to our data. Variant chr16-2104541-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-3.34 with no splicing effect.
BS2
?
High AC in GnomAd4 at 56 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.8118C>T | p.Thr2706= | synonymous_variant | 22/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.8118C>T | p.Thr2706= | synonymous_variant | 22/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.000374 AC: 56AN: 149828Hom.: 0 Cov.: 20
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GnomAD3 exomes AF: 0.000463 AC: 71AN: 153352Hom.: 0 AF XY: 0.000495 AC XY: 41AN XY: 82760
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GnomAD4 exome AF: 0.000579 AC: 829AN: 1430936Hom.: 0 Cov.: 30 AF XY: 0.000569 AC XY: 404AN XY: 710478
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GnomAD4 genome ? AF: 0.000373 AC: 56AN: 149946Hom.: 0 Cov.: 20 AF XY: 0.000342 AC XY: 25AN XY: 73202
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Thr2706Thr variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in the dbSNP database (rs375408086) as “NA” and in the NHLBI GO Exome Sequencing Project in 2 of 8238 European American alleles, the Exome Aggregation Consortium database (March 14, 2016) in 8 of 17150 chromosomes (freq. 0.0005) in the following populations: European (Non-Finnish) in 5 of 6284 chromosomes (freq. 0.0008), South Asian in 2 of 7952 chromosomes (freq.0.0003), African in 1 of 1292 chromosomes (freq. 0.0008), increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Thr2706Thr 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Polycystic kidney disease, adult type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
PKD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 20, 2020 | 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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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