16-2090335-ACTC-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_001009944.3(PKD1):c.12391_12393del(p.Glu4131del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000000685 in 1,460,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 inframe_deletion
NM_001009944.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.55
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001009944.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-2090335-ACTC-A is Pathogenic according to our data. Variant chr16-2090335-ACTC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434007.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr16-2090335-ACTC-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.12391_12393del | p.Glu4131del | inframe_deletion | 45/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.12391_12393del | p.Glu4131del | inframe_deletion | 45/46 | 1 | NM_001009944.3 | P5 | |
PKD1 | ENST00000423118.5 | c.12388_12390del | p.Glu4130del | inframe_deletion | 45/46 | 1 | A2 | ||
PKD1 | ENST00000472577.1 | n.419_421del | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460048Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726264
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GnomAD4 genome Cov.: 34
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34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | In-frame deletion of 1 amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26453610, 33437033) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 25, 2019 | - - |
Polycystic kidney disease Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Glu4131del variant was identified in the literature in 1 of 440 proband chromosomes (freq. 0.002) in a study determining the genotype-phenotype relationship of ADPKD variants; control chromosomes were not tested (Hwang 2016). The same study reported that this variant segregated in 5 or more disease-informative family members (positive and affected, or negative, unaffected, and over 40 years of age). The variant was also identified in ClinVar (our laboratory was the only submitter) and ADPKD Mutation Database (classified as likely pathogenic). The variant was not identified in dbSNP, LOVD 3.0, PKD1-LOVD, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a Glutamic acid (Glu) residue at codon 4131; the impact of this alteration on PKD1 protein function is not known. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Autosomal dominant polycystic kidney disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at