rs377692278
Positions:
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_001009944.3(PKD1):c.11538-11C>T 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 0.00181 in 1,560,680 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0019 ( 3 hom. )
Consequence
PKD1
NM_001009944.3 splice_polypyrimidine_tract, intron
NM_001009944.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00005669
2
Clinical Significance
Conservation
PhyloP100: 0.153
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 -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
Variant 16-2091608-G-A is Benign according to our data. Variant chr16-2091608-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2091608-G-A is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 206 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.11538-11C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000262304.9 | |||
PKD1-AS1 | NR_135175.1 | n.173G>A | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.11538-11C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001009944.3 | P5 | |||
PKD1-AS1 | ENST00000563284.3 | n.70G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00135 AC: 206AN: 152082Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00152 AC: 261AN: 172118Hom.: 0 AF XY: 0.00158 AC XY: 151AN XY: 95820
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GnomAD4 exome AF: 0.00186 AC: 2617AN: 1408480Hom.: 3 Cov.: 32 AF XY: 0.00182 AC XY: 1267AN XY: 697176
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GnomAD4 genome ? AF: 0.00135 AC: 206AN: 152200Hom.: 1 Cov.: 33 AF XY: 0.00128 AC XY: 95AN XY: 74426
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2023 | - - |
Polycystic kidney disease, adult type Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 06, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 03, 2021 | - - |
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.11538-11C>T variant was identified in 5 of 916 proband chromosomes (frequency: 0.005) from French and North American individuals or families with ADPKD (Garcia-Gonzalez 2007, Perrichot 1999, Rossetti 2012). The variant was also identified in dbSNP (ID: rs377692278) “With Likely benign allele”, ClinVar (classified likely benign by Prevention Genetics), and ADPKD Mutation Database (as likely neutral), but was not identified in COGR, and PKD1-LOVD databases. The variant was identified in control databases in 286 of 199042 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of the observations by population include African in 8 of 18176 chromosomes (freq: 0.0004), European Non-Finnish in 223 of 188344 chromosomes (freq: 0.003), South Asian in 9 of 24676 chromosomes (freq: 0.0004), Other in 8 of 5104 chromosomes (freq: 0.002), Latino in 26 of 28456 chromosomes (freq: 0.0009), East Asian in 1 of 15360 chromosomes (freq: 0.00007), and European Finnish in 11 of 10842 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2021 | This variant is associated with the following publications: (PMID: 10987650, 22383692, 17574468) - |
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
Score
Prediction
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