rs200509641
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000262304.9(PKD1):c.8111C>T(p.Ala2704Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,589,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2704T) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000262304.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.8111C>T | p.Ala2704Val | missense_variant | 22/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.8111C>T | p.Ala2704Val | missense_variant | 22/46 | 1 | NM_001009944.3 | ENSP00000262304 | P5 |
Frequencies
GnomAD3 genomes AF: 0.000660 AC: 99AN: 149894Hom.: 0 Cov.: 20
GnomAD3 exomes AF: 0.00142 AC: 223AN: 156602Hom.: 0 AF XY: 0.00177 AC XY: 150AN XY: 84578
GnomAD4 exome AF: 0.000920 AC: 1324AN: 1439004Hom.: 10 Cov.: 30 AF XY: 0.00113 AC XY: 806AN XY: 714798
GnomAD4 genome AF: 0.000660 AC: 99AN: 150012Hom.: 0 Cov.: 20 AF XY: 0.000710 AC XY: 52AN XY: 73196
ClinVar
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 08, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | PKD1: BP4, BS2 - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 02, 2016 | - - |
Polycystic kidney disease, adult type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 02, 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 p.Ala2704Val variant was identified in 1 of 74 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011). The variant was also identified in dbSNP (ID: rs200509641), LOVD 3.0 (2X), and the ADPKD Mutation Database (likely neutral). The variant was not identified in ClinVar, COGR, or PKD1-LOVD databases. The variant was identified in control databases in 239 of 180276 chromosomes at a frequency of 0.001 in the following populations: South Asian in 125 of 23404 chromosomes (freq. 0.005), European in 70 of 73288 chromosomes (freq. 0.001), Finnish in 19 of 15662 chromosomes (freq. 0.001), Other in 8 of 4820 chromosomes (freq. 0.002), Latino in 7 of 25668 chromosomes (freq. 0.0003), East Asian in 4 of 13122 chromosomes (freq.0.0003), African in 3 of 15856 chromosomes (freq. 0.0002), Ashkenazi Jewish in 3 of 8466 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was also identified in one individual from our laboratory with a co-occurring pathogenic variant in PKD2 (c.1704dupT, p.Val569CysfsX4), increasing the likelihood this variant does not have clinical significance. The p.Ala2704 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 benign role for this variant. This variant is classified as likely benign. - |
Autosomal dominant polycystic kidney disease Benign:1
Likely benign, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at