rs13334842
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.603C>T(p.His201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,244,782 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0052 ( 16 hom., cov: 32)
Exomes 𝑓: 0.00056 ( 4 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.77
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=-0.91).
BP6
?
Variant 16-2118389-G-A is Benign according to our data. Variant chr16-2118389-G-A is described in ClinVar as [Benign]. Clinvar id is 433942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118389-G-A is described in Lovd as [Benign]. Variant chr16-2118389-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.77 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152192) while in subpopulation AFR AF= 0.0183 (762/41530). AF 95% confidence interval is 0.0173. There are 16 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 793 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.603C>T | p.His201= | synonymous_variant | 5/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.603C>T | p.His201= | synonymous_variant | 5/46 | 1 | NM_001009944.3 | P5 | |
PKD1 | ENST00000423118.5 | c.603C>T | p.His201= | synonymous_variant | 5/46 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00520 AC: 791AN: 152074Hom.: 16 Cov.: 32
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GnomAD3 exomes AF: 0.00112 AC: 150AN: 133840Hom.: 1 AF XY: 0.000824 AC XY: 60AN XY: 72820
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GnomAD4 exome AF: 0.000563 AC: 615AN: 1092590Hom.: 4 Cov.: 15 AF XY: 0.000480 AC XY: 265AN XY: 551700
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GnomAD4 genome ? AF: 0.00521 AC: 793AN: 152192Hom.: 16 Cov.: 32 AF XY: 0.00491 AC XY: 365AN XY: 74408
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 26, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.His201His variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0 databases nor in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs13334842) as “NA” and in the ADPKD Mutation Database as likely neutral. The variant was further identified in the 1000 Genomes Project in 35 of 5000 chromosomes (frequency: 0.007); and in the Exome Aggregation Consortium database (August 8, 2016) in 9 (1 homozygous) of 11240 chromosomes (frequency: 0.0008) in the African population but not seen the East Asian, European (Non-Finnish), Latino, South Asian or European (Finnish) populations. 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.His201His 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, and HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2020 | - - |
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