rs1016465177
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001009944.3(PKD1):c.-67C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 961,396 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).
Frequency
Genomes: 𝑓 0.0046 ( 12 hom., cov: 31)
Exomes 𝑓: 0.00040 ( 4 hom. )
Consequence
PKD1
NM_001009944.3 5_prime_UTR
NM_001009944.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.315
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 -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
?
Variant 16-2135756-G-A is Benign according to our data. Variant chr16-2135756-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433937.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-2135756-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (682/146822) while in subpopulation AFR AF= 0.016 (656/41024). AF 95% confidence interval is 0.015. There are 12 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 682 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.-67C>T | 5_prime_UTR_variant | 1/46 | ENST00000262304.9 | ||
PKD1 | NM_000296.4 | c.-67C>T | 5_prime_UTR_variant | 1/46 | |||
PKD1 | XM_047434208.1 | c.-67C>T | 5_prime_UTR_variant | 1/48 | |||
PKD1 | XM_047434209.1 | c.-67C>T | 5_prime_UTR_variant | 1/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.-67C>T | 5_prime_UTR_variant | 1/46 | 1 | NM_001009944.3 | P5 | ||
PKD1 | ENST00000423118.5 | c.-67C>T | 5_prime_UTR_variant | 1/46 | 1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00465 AC: 682AN: 146714Hom.: 12 Cov.: 31
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GnomAD4 exome AF: 0.000395 AC: 322AN: 814574Hom.: 4 Cov.: 14 AF XY: 0.000364 AC XY: 137AN XY: 376702
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GnomAD4 genome ? AF: 0.00465 AC: 682AN: 146822Hom.: 12 Cov.: 31 AF XY: 0.00436 AC XY: 312AN XY: 71480
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 c.-67C>T variant was identified in the literature in infant with ADPKD with co-occurring certain pathogenic variant PKD1 (c.8362_8363ins34) (Gilbert 2013), and in one individual in our laboratory with pathogenic variant in PKD2 (c.1663C>T (p.Gln555*)), increasing the likelihood that the c.-67C>T variant does not have clinical significance. The variant was also identified in dbSNP (ID: rs1016465177) as "With Likely benign allele", ClinVar (classified as likely benign by one submitter), and ADPKD Mutation Database (as likely neutral). The variant was identified in control databases in 123 of 25272 chromosomes at a frequency of 0.0049 (Genome Aggregation Database Feb 27, 2017), and observed in the following populations: African in 123 of 8194 chromosomes (freq: 0.015), European in 2 of 13610 chromosomes (freq. 0.00014), while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and 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, 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
RBP_binding_hub_radar
RBP_regulation_power_radar
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