rs551353498
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting
The ENST00000262304.9(PKD1):c.238C>T(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,464,496 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. R80Q) 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 -17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.238C>T | p.Arg80Trp | missense_variant | 2/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.238C>T | p.Arg80Trp | missense_variant | 2/46 | 1 | NM_001009944.3 | ENSP00000262304 | P5 | |
PKD1 | ENST00000423118.5 | c.238C>T | p.Arg80Trp | missense_variant | 2/46 | 1 | ENSP00000399501 | A2 | ||
ENST00000562027.1 | n.150G>A | non_coding_transcript_exon_variant | 1/2 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152192Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00158 AC: 216AN: 136402Hom.: 7 AF XY: 0.00219 AC XY: 162AN XY: 74078
GnomAD4 exome AF: 0.000528 AC: 693AN: 1312186Hom.: 14 Cov.: 22 AF XY: 0.000781 AC XY: 509AN XY: 651462
GnomAD4 genome AF: 0.000236 AC: 36AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74470
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2021 | See Variant Classification Assertion Criteria. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 19, 2018 | - - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Arg80Trp variant was not identified in the literature nor was it identified in the ClinVar, COGR, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs551353498), ADPKD Mutation Database (classified indeterminate), and in control databases in 227 of 162048 chromosomes (7 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 4576 chromosomes (freq: 0.0002), Latino in 1 of 24584 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 66780 chromosomes (freq: 0.00005), East Asian in 2 of 11550 chromosomes (freq: 0.0002), and South Asian in 220 (7 homozygous) of 22550 chromosomes (freq: 0.01), it was not observed in the African, Ashkenazi Jewish and European Finnish populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. the variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.1391delT, p.Leu464GlnfsX94), increasing the likelihood that the p.Arg80Trp variant does not have clinical significance. The p.Arg80 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp to the protein; this information is not very predictive of pathogenicity. 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 this variant meets our laboratory criteria to be classified as benign. - |
PKD1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at