16-2091607-G-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_001009944.3(PKD1):c.11538-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,561,070 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 Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 splice_polypyrimidine_tract, intron
NM_001009944.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.003918
2
Clinical Significance
Conservation
PhyloP100: -0.295
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BS2
High AC in GnomAd4 at 20 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 | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.11538-10C>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000262304.9 | |||
PKD1-AS1 | NR_135175.1 | n.172G>T | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.11538-10C>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001009944.3 | P5 | |||
PKD1-AS1 | ENST00000563284.3 | n.69G>T | splice_region_variant, non_coding_transcript_exon_variant | 1/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152116Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000116 AC: 20AN: 172080Hom.: 0 AF XY: 0.000104 AC XY: 10AN XY: 95814
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GnomAD4 exome AF: 0.000240 AC: 338AN: 1408954Hom.: 0 Cov.: 32 AF XY: 0.000249 AC XY: 174AN XY: 697572
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152116Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Polycystic kidney disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 c.11538-10C>A variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs377419559) as "With Likely benign allele" however this is in reference to the ClinVar submission of the PKD1, c.11538-10C>T variant which is classified as likely benign by Prevention Genetic. The c.11538-10C>A variant was also identified in the ADPKD Mutation Database (1 entry classified as likely pathogenic by Athena Diagnostics). The variant was identified in control databases in 22 of 199024 chromosomes at a frequency of 0.0001 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 1 of 18182 chromosomes (freq: 0.00006), Latino in 1 of 28462 chromosomes (freq: 0.00004), European Non-Finnish in 20 of 88366 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.11538-10C>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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 variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at