rs145776888
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001009944.3(PKD1):c.1323G>A(p.Gly441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,601,694 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0083 ( 15 hom., cov: 33)
Exomes 𝑓: 0.00094 ( 25 hom. )
Consequence
PKD1
NM_001009944.3 synonymous
NM_001009944.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.584
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
?
Variant 16-2117551-C-T is Benign according to our data. Variant chr16-2117551-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2117551-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.584 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00826 (1259/152350) while in subpopulation AFR AF= 0.0287 (1192/41584). AF 95% confidence interval is 0.0273. There are 15 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1259 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.1323G>A | p.Gly441= | synonymous_variant | 6/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.1323G>A | p.Gly441= | synonymous_variant | 6/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.00825 AC: 1256AN: 152232Hom.: 15 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1256
AN:
152232
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00208 AC: 414AN: 198918Hom.: 10 AF XY: 0.00162 AC XY: 176AN XY: 108956
GnomAD3 exomes
AF:
AC:
414
AN:
198918
Hom.:
AF XY:
AC XY:
176
AN XY:
108956
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000945 AC: 1369AN: 1449344Hom.: 25 Cov.: 33 AF XY: 0.000847 AC XY: 610AN XY: 720350
GnomAD4 exome
AF:
AC:
1369
AN:
1449344
Hom.:
Cov.:
33
AF XY:
AC XY:
610
AN XY:
720350
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00826 AC: 1259AN: 152350Hom.: 15 Cov.: 33 AF XY: 0.00771 AC XY: 574AN XY: 74490
GnomAD4 genome
?
AF:
AC:
1259
AN:
152350
Hom.:
Cov.:
33
AF XY:
AC XY:
574
AN XY:
74490
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 29, 2022 | - - |
Polycystic kidney disease, adult type Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 28, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 06, 2021 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2019 | This variant is associated with the following publications: (PMID: 22008521, 17574468) - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 21, 2017 | - - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Gly441= variant was identified in 2 of 238 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs145776888) as "With Benign allele", ClinVar (classified as benign by Prevention Genetics and Athena Diagnostics), and in ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 639 of 224986 chromosomes (11 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 579 of 18934 chromosomes (freq: 0.03), Other in 7 of 5530 chromosomes (freq: 0.001), Latino in 41 of 30268 chromosomes (freq: 0.001), European in 10 of 98026 chromosomes (freq: 0.0001), and South Asian in 2 of 26670 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gly441= 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) 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at